Effect of Aloe vera on glycaemic control in prediabetes and type 2 diabetes: a systematic review and meta-analysis

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1 Journal of Clinical Pharmacy and Therapeutics, 2016, 41, doi: /jcpt Review Article Effect of Aloe vera on glycaemic control in prediabetes and type 2 diabetes: a systematic review and meta-analysis N. Suksomboon* PhD, N. Poolsup PhD and S. Punthanitisarn* MSc (Pharm) *Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, and Department of Pharmacy, Faculty of Pharmacy, Silpakorn University, Nakhon-Pathom, Thailand Received 8 February 2016, Accepted 29 February 2016 Keywords: Aloe vera, diabetes mellitus, glycaemic control, prediabetes, systematic review SUMMARY What is known and Objective: Aloe vera (Aloe vera (L.) Burm.f., Xanthorrhoeaceae family) has long been used in folk or traditional medicine for diabetes. Several studies have been conducted on the effect of Aloe vera on glycaemic control, but the results appear inconsistent. We undertook a systematic review and meta-analysis to assess the effect of Aloe vera on glycaemic control in prediabetes and type 2 diabetes. Methods: A comprehensive literature search was conducted through MEDLINE, CENTRAL, CINAHL, Scopus, caltrials.gov, Web of Science, Proquest, LILACS, HerbMed, NAPRALERT and CNKI to the end of January 2016 without language restriction. Historical search of relevant articles and personal contact with experts in the area were also undertaken. Studies were included if they were (1) randomized controlled trials of Aloe vera aimed at assessing glycaemic control in prediabetes or type 2 diabetes and (2) reporting fasting plasma glucose (FPG) or haemoglobin A 1c (HbA 1c ). Treatment effect was estimated with mean difference in the final value of FPG and HbA 1c between the treatment and the control groups. Results and discussion: Eight trials involving 470 patients (235 each for prediabetes and type 2 diabetes) were included. In prediabetes, Aloe vera significantly improved FPG (mean difference 022 mmol/l, 95% CI 032 mmol/l to 012 mmol/l, P < 00001), with no effect on HbA 1c (mean difference 2 mmol/ mol, 95% CI 5 mmol/mol to 1 mmol/mol). Aloe vera may improve glycaemic control in type 2 diabetes, with a marginal improvement in FPG (mean differences 117 mmol/l, 95% CI 235 mmol/l to 000 mmol/l, P = 005) and a significant improvement in HbA 1c (mean difference 11 mmol/mol, 95% CI 19 mmol/mol to 2 mmol/mol, P = 001). What is new and Conclusions: The current evidence suggests some potential benefit of Aloe vera in improving glycaemic control in prediabetes and type 2 diabetes. However, given the limitations of the available evidence and the high heterogeneity in study results, high-quality, well-powered randomized controlled trials using standardized preparations are needed to quantify any beneficial effects of Aloe vera on glycaemic control. WHAT IS KNOWN AND OBJECTIVE Prediabetes is defined as impaired fasting glucose and/or impaired glucose tolerance. Individuals with prediabetes are at relatively high risk of developing diabetes in the future. The pathogenesis of prediabetes and type 2 diabetes involves insulin resistance and defective beta cell function in secreting insulin. 1,2 More than half of type 2 diabetes patients are unable to control their blood glucose using available oral antihyperglycaemic agents. A variety of herbs including Aloe vera (Aloe vera (L.) Burm.f., Xanthorrhoeaceae family) have been used in folk or traditional medicine for diabetes. 3 5 It has been reported to possess hypoglycaemic activity through direct glucose lowering effect and improving insulin resistance However, results of clinical trials of the effect of Aloe vera on glycaemic control appear contradictory We performed a systematic review and meta-analysis to evaluate the effect of Aloe vera on glycaemic control in prediabetes and type 2 diabetes to establish its therapeutic benefit in these patients. METHODS Search strategy Reports of clinical trials were identified through a literature search of MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, Web of Science, Proquest, Latin American and Caribbean Health Sciences Literature (LILACS), HerbMed, Natural Products Alert Database (NAPRALERT) and China National Knowledge Infrastructure (CNKI). The bibliographic databases were searched from their respective inceptions up until January 2016 without language restriction. The following medical subject headings (MeSH) terms were used: aloe, diabetes mellitus and hyperglycaemia. This was followed by keyword search using [ aloe vera or aloe gel or aloe polysaccharide or acemannan or aloe phytosterols or aloe elements ] AND [ prediabetes or impaired plasma glucose or impaired glucose tolerance ]. Historical search of relevant articles and personal contact with experts in the area were also undertaken. Non-English-language articles were translated into English. Correspondence: N. Poolsup, Department of Pharmacy, Faculty of Pharmacy, Silpakorn University, Nakhon-Pathom 73000, Thailand. Tel.: ; fax: ; poolsup_n@su.ac.th, npoolsup@hotmail.com Study selection Eligible studies were selected independently by two reviewers. Disagreements were settled by a third reviewer. The studies were 2016 John Wiley & Sons Ltd 180

2 included if they were (1) randomized controlled trials comparing the effect of Aloe vera versus placebo or no treatment on glycaemic control in prediabetes or type 2 diabetes and (2) reporting fasting plasma glucose (FPG) or haemoglobin A 1c (HbA 1c ). Data extraction and quality assessment Two reviewers independently extracted and recorded the data and assessed the quality of trials using a standardized form. Discrepancies were resolved by a third reviewer. Data extracted were study design, country, participants characteristics, number of participants, FPG and HbA 1c level at baseline, details of treatment and control, duration of treatment, compliance and concomitant interventions. The quality of studies was assessed using the scale developed by Jadad et al. 32 The scale focuses exclusively on three dimensions of internal validity, that is randomization, blinding and patient attrition. The scores range from zero to five. Studies that scored 3 points or more were considered to be of high quality. Statistical analysis Meta-analysis was conducted separately for prediabetes and type 2 diabetes. FPG was primary outcome, and HbA 1c was secondary outcome. Treatment effect was estimated with mean difference in the final value between the treatment and the control groups. The pooled mean difference and estimated 95% confidence interval were calculated using the inverse variance-weighted method. Statistical heterogeneity was assessed using the chi-square and I 2 statistics. Significant heterogeneity existed if the I 2 was >50% or P- value of chi-square test was <010. The fixed-effects model was used to combine the data from individual studies in the absence of significant heterogeneity. The random-effects model was used when heterogeneity existed. Sensitivity analysis was undertaken by excluding low-quality trials. The statistical analysis was performed with Review Manager (RevMan â ) program version 53 (Cochrane Collaboration, Oxford, UK). The significant level was set at P < 005. RESULTS Study selection and study characteristics The study selection process is presented in Fig. 1. In total, 610 articles were initially identified. After title and abstract screening, 593 articles were excluded. Seventeen potentially relevant studies were retrieved. Six studies were further excluded because they were not randomized controlled trials. Of the remaining eleven randomized controlled trials, two were excluded because required data were not extractable, 17 and patients with type 1 and type 2 diabetes were enrolled. 20 One trial identified through clinicaltrials.gov was further excluded as the study results were not available. 22 Finally, eight randomized controlled trials met the inclusion criteria and were included in this systematic review and meta-analysis Of the eight trials, three were conducted in prediabetes or early, non-treated diabetes and five trials enrolled participants with type 2 diabetes The effect of Aloe vera was assessed versus placebo in six trials 24 26,29 31 and against no treatment in two trials. 27,28 Aloe vera preparations used in each trial varied widely. For example, raw crushed aloe leaves were used in one trial 27 and freshly extracted Aloe vera juice in the other. 28 Aloe vera gel powder 29,30 and Aloe vera extract 26,31 were also used. Duration of treatment ranged from 2 to 3 months. Seven trials were published in English 24 26,28 31 and one in Chinese. 27 Six studies were double-blinded 24 26,29 31 and two were nonblinded. 27,28 Two studies in type 2 diabetes were of low quality because they were non-blinded and did not describe method to generate random sequences. 27,28 One study in prediabetes did not report the method used to generate random sequences, did not use double-dummy technique and provided no details on reasons of participants withdrawal, thus being of low quality. 25 Characteristics of and co-intervention used in individual trials are shown in Table 1. Two of three trials in prediabetes were three-arm comparisons between two treatments and control group. 25,26 In the meta-analysis, the data from different treatments were combined and treated as the treatment group. Meta-analysis of effect on glycaemic control FPG. Three trials contributed to data on the effect of Aloe vera on FPG in prediabetes and five trials in type 2 diabetes Aloe vera significantly reduced FPG in prediabetes (mean difference 022 mmol/l, 95% CI 032 mmol/l to 012 mmol/l, P < 00001). In type 2 diabetes, FPG was marginally reduced (mean difference 117 mmol/l, 95% CI 235 mmol/l to 000 mmol/l, P = 005) (Fig. 2). HbA 1c. Two studies with 113 prediabetes participants 25,26 and four studies with 197 type 2 diabetes patients provided poolable data on HbA 1c. No effect was detected in prediabetes, whereas HbA 1c level was decreased significantly in type 2 diabetes (mean difference 11 mmol/mol, 95% CI 19 mmol/mol to 2 mmol/ mol, P = 001) (Fig. 3). Sensitivity analysis Among the included studies, one study in prediabetes 25 and two in type 2 diabetes 27,28 were of low quality. Sensitivity analysis excluding these studies demonstrated that the effect of Aloe vera in prediabetes remained unchanged. It was superior to placebo in reducing FPG (mean difference 022 mmol/l, 95% CI 033 mmol/l to 012 mmol/l, P < 00001). The effect on FPG in type 2 diabetes became non-significant (mean difference 045 mmol/l, 95% CI 196 mmol/l to 106 mmol/l), whereas the effect on HbA 1c remained significant, but slightly weakened (mean difference 8 mmol/mol, 95% CI 15 mmol/mol to 0 mmol/mol, P = 004). DISCUSSION In this meta-analysis, FPG was used as the primary outcome as it was universally reported in all of the included trials, whereas HbA 1c was not generally reported. Our meta-analysis showed that Aloe vera possibly improved glycaemic control in prediabetes and type 2 diabetes. It may be beneficial when used as a supplement particularly in patients with type 2 diabetes in whom a promising response on FPG and HbA 1c was observed. In prediabetes, Aloe vera lowered FPG only, with an absence of effect on HbA 1c. Several mechanisms of action have been postulated. Aloe vera attenuated the absorption of glucose in the gastrointestinal tract after consuming food. 14 It also stimulated glucose catabolism and suppressed glucose production. 7,11,13 Glucose storage and utilization were enhanced. 7,13 Aloe formula including processed Aloe vera gel (PAG), aloesin, Aloe QDM (100 mg/kg of PAG containing 2% aloesin) and Aloe QDM complex (Aloe QDM plus 500 mg/kg 181

3 MEDLINE, CENTRAL, CINAHL, Scopus, ClinicalTrials.gov, Web of Science, Proquest, LILACS, HerbMed, NAPRALERT,CNKI, expert contact and historical search up to January 2016 Article identified and screened (n = 610) Article excluded (n = 593) Full text articles retrieved (n = 17) Studies excluded (n = 6): Not randomized controlled trials 15,16,18,19,21,23 Randomized controlled trials assessed for eligibility (n = 11) Studies excluded (n = 3): Data not extractable 17 Included type 1 and type 2 diabetes 20 Study results not available 22 Randomized controlled trials included in systematic review and meta-analysis (n =8) Fig. 1. Study selection process. Chromium (Cr)-enriched yeast containing 02% Cr) have been demonstrated to be involved in the activation of AMP kinase via the same mechanism of action as one of antihyperglycaemic agents, namely metformin. 12 As the maximum effects of metformin in decreasing FPG and HbA 1c have been reported at approximately 6 months of administration in a placebo-controlled study, 33 it is possible that the effect of Aloe vera on FPG and HbA 1c would have been more pronounced if the treatment had lasted at least 6 months. A significant reduction in HbA 1c by 11 mmol/mol, or 10%, with Aloe vera observed in our meta-analysis may provide additional clinical benefit as each 1% reduction in mean HbA 1c has been reported to reduce the risk by 21% for any endpoint or death related to diabetes, 14% for myocardial infarction and 37% for microvascular complications. 34 It is worth mentioning that type 2 diabetes patients participating in the included trials were primarily treated with antihyperglycaemic agents (Table 1), whereas participants with prediabetes or early diabetes were antihyperglycaemic agents-na ıve. An observed absence of effect on HbA 1c in prediabetes was expected and may be explained by normal or near normal level at baseline among these patients together with a short duration of study. Aloe vera seemed to be well tolerated. Most studies reported that no patients experienced adverse effects. 25,27,29,30 One trial described two cases of diarrhoea or vomiting after Aloe vera juice consumption leading to dropouts. 28 Diarrhoea may be associated with the laxative effect of anthraquinones in Aloe vera leaves. Other trial reported one adverse event leading to withdrawal but did not provide additional details. 24 Safety did not seem to have been evaluated at all in two trials. 26,31 Pooling data on safety were not possible as adverse effects were not systematically recorded or reported. Reported adverse effects of oral use of Aloe vera include hepatitis, hypoglycaemia, diarrhoea, abdominal pain and cramping, muscle weakness and potassium depletion As the studies included in our review lasted 2 or 3 months, long-term safety remains to be determined. Significant heterogeneity was detected among the results of type 2 diabetes trials. As described earlier, a wide range of Aloe vera preparations and dosages were used. In most reports, details of active constituents were not given. Two studies used aloe leaf gel powder containing acemannan. 29,30 The remaining studies used raw crushed aloe leaves, 27 freshly extracted Aloe vera juice 28 or Aloe vera extract tablet. 31 Most trials were conducted in Iran. 26,29 31 It is well recognized that the amounts of phytoconstituents may vary among herbs grown in different geographical areas. In addition, participants characteristics and variation in co-interventions and compliance may have a role to play. The majority of the included 182

4 Table 1. Characteristics of the included studies Study Country Design Age (years) Duration of DM (year) Baseline FPG (mmol/l) Baseline HbA1c (mmol/mol) Intervention (N) Duration of treatment (months) Compliance Jadad s score Prediabetes Choi et al. 24 South Korea DB NA Aloe QDM complex a capsule 700 mg 2 capsules twice daily (68) or placebo (68) Devaraj et al. 25 USA DB NA UP780 b capsule 500 mg (15) or AC952 c capsule 500 mg (15) twice daily or placebo (15) Alinejad-Mofrad Iran DB NA Aloe vera extract capsule 300 mg (24) or et al mg (24) twice daily or placebo (24) 2 75% % 2 2 NR 4 T2DM Liu et al. 27 China Non-blind NR Raw crushed Aloe leaves (whole leaves) 15 g twice daily (19) or no treatment (19) Arora et al. 28 India Non-blind NR NR Freshly extracted Aloe vera juice 150 ml once daily (14) or no treatment (12) Huseini et al. 29 Iran DB Aloe gel powder capsule 300 mg twice daily (33) or placebo (34) Huseini et al. 30 Iran DB Aloe gel powder capsule 300 mg twice daily (35) or placebo (35) Zarrintan et al. 31 Iran DB NR Aloe vera extract tablet 1000 mg daily (22) or placebo (22) 3 NR 2 3 NR 2 2 Monitored, but not reported 2 Monitored, but not reported 2 NR Study Inclusion criteria Co-intervention Notes Prediabetes Choi et al. 24 Prediabetes or early non-treated diabetes Obesity (body mass index 25 kg/m 2 ) or abdominal obesity (waist circumference 90 cm for men and 85 cm for women) Impaired FPG ( 100 mg/dl) or impaired glucose tolerance (2-h OGTT 140 mg/dl) Be able to control blood glucose levels by using lifestyle modification (FPG <180 mg/dl and HbA 1c <8.0%) None No differences between groups in the intake of fiber and calories from carbohydrate, protein or fat. (continued) 183

5 Table 1 (continued) Study Inclusion criteria Co-intervention Notes Devaraj et al. 25 Age years None Prediabetes, defined as impaired FPG ( mg/dl) or impaired glucose tolerance (2-h OGTT mg/dl) plus any 2 of the followings : 1. Waist circumference >35 inches in women and >40 inches in men 2. Triglyceride (TG) levels >150 mg/dl 3. HDL cholesterol <40 mg/dl in men and <50 mg/ dl in women 4. Systolic blood pressure/diastolic blood pressure >130/85 mmhg Willing to maintain a normal diet and exercise at least 100 min per week Alinejad-Mofrad et al. 26 Age years None Patients were asked not to have any FPG mg/dl, HbA1c % change in their diet and routine Triglyceride (TG) mg/dl activities. Total cholesterol (TC) mg/dl HDL cholesterol <35 mg/dl LDL cholesterol mg/dl Body mass index (BMI) No use of any lipid-lowering treatment No serious stress during last 2 months T2DM Liu et al. 27 Type 2 diabetes with early diabetic nephropathy Insulin or gliquidone Diabetes education and dietary control Arora et al. 28 Type 2 diabetes Oral antihyperglycaemic agents Dietary control and exercise as per physician s advice (continued) 184

6 Table 1 (continued) Study Inclusion criteria Co-intervention Notes Huseini et al. 29 Type 2 diabetes Age years FPG mg/dl and HbA1c 7 9% despite taking glyburide 10 mg/day plus metformin 1000 mg/day everyday Taking glyburide 10 mg/day plus metformin 1000 mg/day everyday Newly diagnosed dyslipidaemia with LDL >100 mg/ dl and/or triglyceride >150 mg/dl Huseini et al. 30 Type 2 diabetes Age years FPG mg/dl, HbA 1c % Resistant to the combination of oral antihyperglycaemic agents needing insulin but refusing it Zarrintan et al. 31 Type 2 diabetes for at least 6 months Age years Taking only blood glucose-lowering drugs, not using insulin Glyburide 10 mg/day and metformin 1000 mg/day Dietary control Combination of oral antihyperglycaemic agents (glyburide, metformin, gliclazide, acarbose, pioglitazone and repaglinide) Dietary control Oral antihyperglycaemic agents Dietary control Treatment, diet, physical activity remained unchanged throughout the study. Treatment, diet, physical activity remained unchanged throughout the study. a Aloe QDM complex = processed Aloe vera gel 147 mg/cap + 95% aloesin powder 3 mg/cap + yeast chromone 125 mg/cap + excipients 425 mg/cap. b UP780 = Aloe vera inner leaf gel powder standardized with 2% aloesin. c AC952 = Aloe vera inner leaf gel powder. Data are mean or mean SD. DB, double-blind; NA, not applicable; NR, not reported. 185

7 Fig. 2. Meta-analysis of effect on fasting plasma glucose. Fig. 3. Meta-analysis of effect on HbA 1c. studies did not report on the patients compliance ,31 Although some studies did monitor compliance, the actual results were not reported. 29,30 There are also other limitations in the included trials. Firstly, most enrolled a small number of participants, thus lacking statistical power. Indeed, none of the studies reported any power calculation. Secondly, most of the type 2 diabetes patients participating in the trials had been prescribed antihyperglycaemic drugs and dietary control, but only two studies confirmed that treatment, diet and physical activity were kept unchanged throughout the study period. 29,30 Finally, the methodological quality varied, with three trials being of low quality. 25,27,28 Two studies in type 2 diabetes were non-blinded, 27,28 and one in prediabetes was double-blinded but did not use the doubledummy technique. 25 This is especially important as performance bias may occur. Bias in favour of treatment may also be introduced in those trials in which there seemed to be an imbalance in baseline FPG between the Aloe vera and the control groups, and statistical testing was not conducted to assess the comparability of the two groups. 27,28 This was evident in our sensitivity analysis. A nonsignificant effect on FPG in type 2 diabetes was observed when low-quality studies were excluded. The effect on HbA 1c remained significant, but slightly diminished. Some limitations of this meta-analysis should be highlighted. First, there was significant heterogeneity among the results of the studies included. In addition, only published trials were included and reporting bias cannot be ruled out although we considered both English and non-english publications. Funnel plot and Egger s method were not performed to assess publication bias as 186

8 the number of studies included in each meta-analysis was too small to permit reasonable use of those methods. Finally, antihyperglycaemic agents and non-pharmacologic management were used in the studies of type 2 diabetes, making it difficult to isolate the effect of Aloe vera. However, such combination treatment is common in clinical practice. WHAT IS NEW AND CONCLUSION The current evidence suggests a possible effect of Aloe vera on glycaemic control in prediabetes and type 2 diabetes. However, given the poor quality of the limited evidence available, and the considerable heterogeneity seen in the study results, welldesigned, well-powered randomized controlled trials using standardized preparations are needed to better quantify any beneficial effects and their clinical relevance. Various components of Aloe vera and appropriate dosage should be further explored. HbA 1c and postprandial glucose should be commonly assessed and reported. 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