Background

Diabetes mellitus is a metabolic disorder that affects approximately 285 million adults worldwide.1 It has been indicated that this number would approximately double by 2030, which will equate to 7.7% of the world population.2 Diabetes mellitus is a physiological dysfunction characterized by hyperglycemia due to insulin resistance, improper insulin secretion from the pancreas or large amounts of glucagon excretion.3 There are different types of diabetes, some more common than others. The most common type of diabetes is type 2 diabetes mellitus (T2DM) that develops from pre-diabetes. Pre-diabetes is described as the presence of a blood glucose level higher than the normal range, but not high enough to be categorized as diabetes.4 Type 2 diabetes mellitus is described as the presence of high blood glucose levels due to impaired glucose regulation as a result of improper functioning of the pancreatic beta cells and insulin resistance.3 Poor management of diabetes results in long-term complications affecting the retina, kidney and nervous system.5,6 It is reported that diabetes is the most common cause of blindness, heart disease and amputations in people with the disease.7-9

Management of diabetes involves medical treatment including pharmacotherapy or anti-diabetic medications for the effective management of T2DM. There are different types of pharmacotherapies available for the treatment of diabetes. These include biguanides, sulfonylureas, non-sulfonylureas, alpha-glucosidase inhibitors, thiazolidinedione or insulin sensitizer, intestinal lipase inhibitor, glucagon-like-peptide-1-receptor agonist, dipeptidyl-peptidase-4 inhibitor, sodium-glucose-co-transported type 2 (SGLT2) inhibitors and insulin therapy.10-15

Biguanide (metformin) is the most commonly used pharmacotherapy for the treatment of T2DM. Metformin acts by reducing the glucose output in the liver by increasing the liver and muscle insulin reactivity.12 Metformin has a positive impact on lowering HbA1c by 0.5-1.0%.15 Biguanides also have some side effects on the human body such as gastrointestinal problems (nausea, diarrhea and abdominal pain) most commonly, and lactic acidosis very rarely.15 Alpha-glucosidase inhibitors, such as Acarbose, decrease postprandial blood glucose and insulin concentrations by inhibiting conversion of oligosaccharides to monosaccharides in the intestine.16 Alpha-glucosidase inhibitors play an important role in lowering HbA1c by 0.5-1.0%.16 Alpha-glucosidase inhibitors do not cause hypoglycemia and weight gain, but they can lead to gastrointestinal problems (flatulence, abdominal pain and diarrhea).17 Alpha-glucosidase inhibitors are contraindicated in people who have irritable bowel syndrome, and chronic liver and kidney diseases due to a higher risk of gastrointestinal problems, chronic hepatitis and lactic acidosis.17

Sulfonylureas such as glipizide, glyburide and glimepiride are another pharmacotherapy treatment that stimulates insulin secretion from the pancreatic cells and improves hyperglycemia.18 Sulfonylurea binds to sulfonylurea receptor-kir6.2, a regulatory protein in pancreatic cells, which causes the closure of adenosine triphosphate-dependent potassium channels and prevents the outward flow of potassium ions from beta cells.19 Sulfonylureas have the ability to lower HbA1c by 1.0-1.5%.20 The main side effects of this drug are hypoglycemia, weight loss and myocardial events.19 A cohort analysis of patients with T2DM who used sulfonylurea for diabetes management in America concluded that these patients were at 30% higher risk for re-admission to hospital compared to those taking other oral anti-hyperglycemic agents.21 Sulfonylureas are contraindicated in patients who have liver and kidney diseases due to the high risk of chronic hepatitis and lactic acidosis.19 Non-sulfonylureas such as repaglinide and nateglinide maintain blood sugar levels by increasing acute insulin secretions from pancreatic beta cells.22,23 Non-sulfonylureas also have a positive impact on HbA1c as the decrease in HbA1c with repaglinide ranges from 0.5% to 1.5%.22,23 The main side effects of repaglinide and nateglinide are hypoglycemia and weight gain.22,23 However, non-sulfonylureas are contraindicated in patients who have kidney and liver diseases because of the high risk of lactic acidosis and chronic hepatitis.

Thiazolidinediones maintain blood sugar levels by increasing adipose and muscle insulin sensitivity, specifically in the peripheral tissues.24 Thiazolidinedione also have HbA1c-lowering capacity that ranges from 1.0 to 1.5%.25 Thiazolidinediones can lead to increase in weight, swelling, anemia, fluid retention, pulmonary edema and chronic heart failure.25 Thiazolidinediones are contraindicated in patients with liver diseases and chronic heart failure due to the high risk of congestive heart failure.25 Intestinal lipase inhibitors such as Orlistat are used to manage blood sugar levels by reducing fact absorption and so facilitate weight loss or cause weight loss.26 Intestinal lipase inhibitors also have effects on HbA1c as they decrease HbA1c by 0.3-0.9%.27 There are some side effects of using intestinal lipase inhibitors such as gastrointestinal problems and reduced absorption of fat-soluble vitamins.26 These medications are contraindicated in patients with malabsorption syndrome and cholestasis due to a high risk of gastrointestinal side effects.28

Glucagon-like peptide-1 receptor agonists such as Exenatide and Liraglutide improve glycemic control by improving insulin secretion.29 Glucagon-like peptide-1 also has side effects such as gastrointestinal problems, pancreatitis and risk of minor hypoglycemia.30 Dipeptidyl peptidase-4 inhibitors such as Sitagliptin and Alogliptin improve glycemic control by increasing the availability of endogenous peptides.31 The most common side effects are urinary tract infection, headache and nasopharangitis, and less common side effects are hypoglycemia and weight loss.31 Sodium-glucose-co-transported type 2 inhibitors such as dapagliflozin and canagliflozin decrease hyperglycemia by increasing kidney glucose secretions and have been demonstrated to be effective for managing diabetes.32,33 The most common side effects associated with SGLT2 are hypoglycemia, urinary tract infection and genital infections.32 Another common pharmacotherapy for diabetes management is insulin therapy, which is a basal therapy that improves glycemic outcome by increasing the basal insulin supply.34 However, it can lead to hypoglycemia and weight gain.34

Many available anti-diabetic medications are effective in the management of T2DM. Oral hyperglycemic agents have advantages over insulin because of fewer allergic reactions, effectiveness in the oral form and they also eliminate the need for daily insulin injections. Despite the availability of extensive recommended therapies for the management of T2DM, the compliance with these therapies is very low. A study reported that less than 50% T2DM patients obtain appropriate glycemic control.35 A systematic review of adherence with medication for diabetes reported that compliance with oral hypoglycemic agents medication therapies ranged from 36% to 93% within six to 24 months of treatment period.36 An observational record-based study conducted on 1099 people with diabetes mellitus reported a 71% average adherence to insulin treatment.37 In addition, another retrospective review conducted on 209 T2DM patients reported a highest 67% compliance with single insulin therapy, and only 39% compliance in patients with insulin and oral hypoglycemic agents.38 Decreased adherence to conventional treatment therapies can result in poor health outcomes, hence an important effect on the economic cost of a healthcare system.39

As this review has indicated, modern conventional therapies have numerous side effects. These side effects, combined with the chronicity of diabetes, can result in poor compliance with pharmacological treatment, which in turn can lead to compromised health benefits, and hence significant economic consequences. Research has also established that pharmacotherapy in addition to lifestyle modifications can be effective in the management of diabetes. Lifestyle modifications in terms of regular exercise, maintenance of ideal body weight, diet modifications and self-monitoring of blood glucose levels have been reported as effective strategies for diabetes management.40

There is an emerging trend worldwide for the use of complementary and alternative medications, in particular biologically based therapies (dietary supplements, herbal, plant-based and botanical products)41 and, more specifically, plant-based products to improve the blood glucose levels. The commonly used plant products for the treatment of diabetes include bitter gourd (Momordica charantia), cinnamon (Cinnamomum verum), sweet potato (Ipomoea batatas), garlic (Allium sativa), fenugreek (Trigonella foenum-graecum) and Aloe vera (Aloe barbadensis).42 Given the increasing use of the various plant products, systematic reviews of randomized control trials (RCTs) have been conducted on individual plant products to assess their effectiveness in the treatment of diabetes. For example, evidence from a systematic review of RCTs involving 479 participants showed no statistically significant difference in glycemic control among patients with T2DM treated with bitter gourd compared to placebo or metformin at the three-month follow-up.43 Similarly, another systematic review of RCTs involving a total of 577 participants with type 1 and T2DM investigating the effectiveness of cinnamon (C. verum) showed no statistically significant difference in fasting blood glucose (FBG) and glycosylated hemoglobin (HbA1c) between those who received cinnamon and the control group.36

The results of another systematic review of RCTs investigating the effects of sweet potato (I. batatas) in participants with T2DM showed a significant improvement in HbA1c in those receiving sweet potato compared to placebo at the six weeks and five months follow-up.44 A recent review on garlic (A. sativa) showed a significant reduction in insulin resistance in those receiving garlic.45 Results from an RCT conducted with 25 type 2 diabetic patients indicated that the use of fenugreek seeds improves glycemic control and reduces insulin resistance.46

There are some studies that have reported the use of complementary and alternative therapies for the management of diabetes;47-50 however, no systematic review was identified during the literature search for this paper that discussed the effect of A. vera on diabetes management. A. vera has been used in different countries worldwide for its healing, soothing and rejuvenating properties.51A. vera is a succulent plant that belongs to the Liliaceal family and comprises more than 360 species.52,53 Aloe barbadensis is the most commonly used species of A. vera for the management of health conditions.52,53A. vera contains 75 nutrients such as minerals (calcium, magnesium, sodium, potassium, manganese, copper, zinc, chromium and iron) and vitamins (vitamin A, C, E, B12 and folic acid) with antioxidant properties, amino acids (amylase and lipase), sugars (monosaccharide, polysaccharide and acemannan), enzymes (aliiase, alkaline phosphatase, amylase, bradykinase, carboxypeptidase, catalase, cellulase, lipase and peroxidase) sterols, salicylic acid, lignin and saponins.54 These nutrients have antioxidant, muscle repairing, immunomodulating, antiviral, anti-inflammatory, sugar and fat metabolism, blood thinning, pain killing and antiseptic properties.54

The A. vera plant contains fleshy leaves, yellow tubular flowers and fruits with seeds.53,54 Each leaf has three layers such as outer, middle and inner. The outer layer is very significant because this is where synthesis of the 75 nutrients occurs. A. vera gel present in the leaves is the most common component of the A. vera plant used for the treatment and management of the diabetes. The gel contains phytosterols that have been reported to reduce FBG among diabetic mice.55,56 A literature review of selected research indicated that the oral intake of A. vera is effective in improving glycoprotein metabolism in diabetic animals.57 Literature reviews on A. vera leaf gel reported that oral intake of A. vera is effective for improving FBG in human beings.52,53 A range of studies conducted on human beings indicated a positive effect of A. vera on diabetes management.58-60 Although the exact mechanism of the action of A. vera is unclear, it has nevertheless been reported that A. vera triggers insulin secretion from the pancreatic beta cells.61 It is worth noting that a clinical trial testing the effects of A. vera gel on diabetic mice reported that A. vera gel improved insulin resistance by reducing toxic effects of lipids in the liver.62

Another trial affirmed the positive effect of A. vera on diabetes management on rat animals.54 In a placebo controlled trial undertaken on 15 participants with diabetes, the use of A. vera demonstrated a significant reduction in HbA1c levels.49 In contrast, a clinical trial undertaken on 72 diabetic participants with T2DM demonstrated no difference in HbA1c levels.47 An initial search of the CINAHL, PubMed and Scopus databases was conducted, and no systematic reviews or protocols that investigated the effect of A. vera on the management of diabetes were identified. With the emergence of new data on A. vera and a lack of consensus on the glycemic effects of A. vera, a thorough systematic review is warranted. Therefore, the aim of this systematic review is to investigate the effectiveness of A. vera on glycemic outcomes in people with diabetes mellitus.

Inclusion criteria

Types of participants

The current review will consider studies that include adult males and females aged 18 years and over with T2DM with or without anti-diabetic medications for the management of their diabetes and regardless of the duration of their condition. Diagnostic criteria for T2DM will include FBG level >=7.0 mmol/L on two separate tests and HbA1c >= 6.5% on two separate tests.63 This review will also consider studies that include adult males and females aged 18 years and over with pre-diabetes. Diagnostic criteria for pre-diabetes will include FBG level range from 5.6 mmol/L to 6.9 mmol/L and HbA1c ranges from 5.7% to 6.4%.64 The review will exclude patients with type 1 diabetes mellitus due to the complex treatment of type 1 diabetes mellitus.

Definition of terms

Type 1 diabetes mellitus is also called juvenile or insulin-dependent diabetes mellitus, in which the pancreas secretes small amounts of insulin or there is a lack of insulin production. Insulin hormones help glucose to enter body cells, which then results in energy production. T2DM is also called non-insulin-dependent diabetes mellitus (NIDDM) and is caused by increased blood glucose levels due to insulin resistance or lack of insulin. Pre-diabetes is diagnosed when blood glucose levels are elevated but are not high enough to consider NIDDM.

Types of interventions

The current review will consider studies that evaluate the oral use of A. vera for a maximum of four weeks in pre-diabetes and T2DM management. The review will also consider studies that concentrate on 300 mg oral A. vera gel capsules twice a day for the management of their diabetes mellitus.

The following comparisons will be made:

* Vera plus anti-diabetic medication versus placebo plus anti-diabetic medications.

* Vera plus anti-diabetic medications versus anti-diabetic medications.

Outcomes

The current review will consider studies that include glycemic outcomes, including FBG (mmol/L) and HbA1c (mmol/mol) measured for a minimum of four weeks. Other relevant clinical outcomes, including incidence of hypoglycemia, hyperglycemia and gastrointestinal complications such as diarrhea, will be included.

Types of studies

The quantitative component of the review will consider experimental study designs including randomized and pseudo-RCTs. In the absence of RCTs, other designs including non-randomized comparative studies, cohort studies and case-control studies will be included.

Search strategy

The search strategy will aim to find both published and unpublished studies. A three-step search strategy will be utilized in this review. An initial limited search of CINAHL, PubMed and Scopus will be undertaken followed by an analysis of the text words contained in the title and the abstract, and of the index terms used to describe the article. A second search using all identified keywords and index terms will then be undertaken across all included databases. Databases will be searched as far back as possible. The third step will be a search of the reference lists and bibliographies of all relevant articles. The initial search terms will include A. vera, diabetes mellitus, FBG, glycemic outcomes and HbA1c. Databases that will be searched for published studies will include CINAHL, PubMed, Current Contents, Cochrane Central Trials, MEDLINE, Expanded Academic Index and Embase. Databases searched for unpublished trials will include Dissertation Abstract International and clinical trials.gov. Studies published between 1966 to the present will be included to identify previous literature published on the topic. Another reason of limiting the search to 1996 is that literature on the effect of A. vera on diabetes mellitus was initially published in 1996, and no literature on the same topic was identified before the year 1996. Studies published only in the English language will be considered for inclusion in this review.

Assessment of methodological quality

Papers selected for retrieval will be assessed by two independent reviewers for methodological validity prior to inclusion in the review using the standardized Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI).65 Any disagreements that arise between the reviewers will be resolved through discussion or with a third reviewer.

Data extraction

Quantitative data will be extracted from papers included in the review using the standardized data extraction tool from JBI-MAStARI65 to identify the effect of A. vera (Aloe barbadensis) on glycemic outcomes in human patients with pre-diabetes and T2DM. Data will be extracted from the non-experimental studies using data extraction tools from JBI. The data extracted will include specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives. Data extraction from the included papers will be undertaken and summarized independently by two reviewers. If any data are missing from the paper report, attempts will be made to obtain them by contacting the authors.

Data synthesis

Quantitative data will, where possible, be pooled in statistical meta-analysis using RevMan v5.2 (Copenhagen: The Nordic Cochrane Centre, Cochrane). Cochrane Collaboration, 2014. All results will be subject to double data entry. Effect sizes expressed as odds ratio (for categorical data) and weighted mean differences (WMDs) (for continuous data) and the 95% confidence intervals (CIs) will be calculated for analysis. Considering the populations, interventions and outcomes between the studies will assess clinical heterogeneity. Statistical heterogeneity will be investigated by calculating the I² statistic, and if this indicates a high level of heterogeneity among the trials included in an analysis, a random effects meta-analysis will be preferred for the overall summary. Relative risks and 95% CIs will be calculated for dichotomous data. Analysis of continuous data will be undertaken using the mean and standard deviation values to derive WMDs and their 95% CIs. If 10 or more studies are included for a particular outcome, a funnel plot will be presented, with the aim of looking for signs of asymmetry with respect to publication bias. Where synthesis is inappropriate, a narrative overview will be undertaken.

References