Effectiveness of Ginger in the Treatment of Type 2 Diabetes Mellitus: A Pilot Study of the Randomized Clinical Trial Type*

* This article derives from the doctoral thesis entitled “Efeito do gengibre (Zingiber officinale) no controle glicêmico e lipêmico de pessoas com diabetes tipo 2: ensaio clínico randomizado duplo-cego controlado por placebo”, presented to the Graduate Program in Nursing at the Universidade Federal do Ceará and funded by the Conselho Nacional de Desenvolvimento Científico e Tecnológico, Grant: 310496/2017–9. Available in: http://www.repositorio.ufc.br/handle/riufc/36485.


Introduction
Even after years of research, Type 2 Diabetes Mellitus (T2DM) is still characterized as one of the main chronic diseases in the world (1). When diagnosed with this disease, the patient generally presents metabolic dysregulations that require continuous and expensive care. Currently, the clinical treatment is mainly focused on pharmacological interventions. However, oral antidiabetic medications are commonly associated with unwanted adverse effects that lead to discontinuation of therapy or clinical inertia, influencing the chronicity degree of the disease (2).
With this in mind, a number of research studies have been developed in an attempt to incorporate strategies that can minimize the lack of medication adherence and improve glycemic control. Given the above, experts have highlighted the antidiabetic properties of food supplements traditionally used in different cultures around the planet. Among them, ginger (Zingiber officinale) stands out, which has been used both as a spice, especially in cooking, for its spicy acid flavor and unique aroma, and as herbal medicine in the treatment of arthritis, non-alcoholic fatty liver disease, primary dysmenorrhea, seasickness and oncological therapies (3).
In addition to that, evidence has shown that ginger has the potential to reduce glycemic levels in people with T2DM, as well as its complications, as it interacts with different molecular pathways involved in the genesis of the disease, such as the inhibition of several transcriptional pathways, lipid peroxidation, reduction of carbohydrate metabolizing enzymes, and activation of the capacity of the antioxidant enzymes and low-density lipoprotein receptors. This cascade of events is reflected in the increase in insulin synthesis, in the reduction of insulin resistance, and in the accumulation of fat, in addition to the protective effects against complications arising from diabetes (4)(5)(6)(7)(8)(9).
A meta-analysis showed that ginger can be considered an effective and promising adjuvant in the treatment of T2DM, since it does not present important adverse events and has been beneficial in attenuating the glycemic, lipid or even anthropometric levels of people with the disease. Despite this, researchers continue to recommend new studies to explore the therapeutic capacity of this product (3). In Brazil, studies on this topic are scarce and, for this reason, the objective of this research was to analyze the effectiveness of ginger in reducing glycemic, lipid and anthropometric levels in people with T2DM.

Type of study
This is a double-blind and placebo-controlled pilot study of the randomized clinical trial type, conducted between October 2017 and January 2018 according to the CONSORT recommendations in a Basic Health Unit (BHU) in the city of Picos, Piauí, Brazil.

Population
The population consisted of 50 individuals with T2DM, registered and monitored in a BHU located in the urban area of the municipality, selected for convenience.

Selection criteria
The inclusion criteria were as follows: individuals aged between 18 and 80 years old; using oral antidiabetic medications; with glycated hemoglobin (HbA1c) between 7 % and 10 %; and with preserved cognitive functions. The age group was determined for the following reasons: 1) individuals over 18 years of age have a better understanding of the disease and could be aware of the relationship of the study; 2) individuals over 80 years old begin to show a decline in their cognitive functions and, in order not to record any bias in this regard, we decided to limit such condition. The participants' cognitive function was assessed by means of the Mini-Mental State Exam. The exclusion criteria were as follows: being allergic to ginger, being pregnant or lactating, being an alcohol or tobacco user, making use of insulin, having severe complications associated with T2DM (chronic kidney, ischemic, autoimmune, liver, severe cardiovascular, gastrointestinal and inflammatory diseases), and the use of ginger supplementation. In addition to that, discontinuity criteria were adopted, namely: hospitalization, having started insulin therapy and/or presenting an allergic reaction.

Definition of the sample
As this is a pilot study in which the researchers involved sought to evaluate the effectiveness and feasibility of the intervention proposal, in addition to estimating the sample size for a future study, the sample of this research was selected for convenience. Of the 50 patients recruited, only 41 were interested in participating and, of these, 17 were excluded for the following reasons: one used daily ginger supplementation; one had ascites; one was on insulin therapy; three reported having severe heart problems, and 11 had HbA1C results < 7 %. Thus, 24 participants were randomized.
The patients were randomly allocated in parallel groups (1:1), one being the experimental (ginger) and the other the control (placebo), each one with 12 people. Randomization was performed based on the HbA1c levels, by a researcher external to the study, using the R software, version 3.1.1. Each number of the randomization sequence was placed inside an envelope, sealed and given to the lead researcher only at the time of vial delivery. In this study, the participants and the lead researcher were kept blind.

Data collection
Before recruitment was started, the researcher responsible for the study met with the team of the BHU chosen and clarified the research to the professionals. The potential participants were recruited over the course of 15 days, through printed invitations made by the researcher and delivered by community health agents. Day and time were scheduled so that patients could attend the BHU.
In addition to the BHU nurse, the responsible researcher was present to clarify the intention of the research and to invite the patients to participate. For those who showed interest, the Free and Informed Consent Form (FICF) was presented, signatures were collected, and the HbA1c test was collected at the site. After this stage, with the results in hand, the patients were instructed on the possibility of participating in the study. Data collection was conducted at the same moment for those who were able and wanted to participate.
For data collection, the questionnaire used included socioeconomic variables (gender, skin color, schooling, occupation, etc.), anthropometric variables (waist circumference, hip circumference, neck circumference, waist-hip ratio, body adiposity index, body mass index, thigh circumference, waist-to-height ratio), clinical variables (blood pressure, time since T2DM diagnosis, episodes of hypo/hyperglycemia in the 30 days prior to collection) and laboratory variables (capillary blood glucose -CBG, fasting blood glucose -FBG, low density lipoprotein -LDL, high density lipoprotein -HDL, total cholesterol -TC, and triglycerides -TG). First, in order to guarantee data uniformity, the responsible researcher trained the other Nursing students and professionals involved in data collection.
As for the anthropometric variables, body weight was measured on an empty stomach, with the participants wearing light clothes and without shoes. Height was also measured with the participants barefooted, using a stadiometer attached to the scale. The body mass index (BMI) was calculated using the weight-toheight ratio (kg/m 2 ), where < 18.5 kg/m 2 indicated low weight; between 18.5 kg/m 2 and 24.9 kg/m2, normal weight; between 25 kg/ m 2 and 29.9 kg/m 2 , overweight; and ≥ 30 kg/m 2 , obesity. Aged patients were classified as underweight when BMI ≤ 22 kg/m 2 , as with appropriate weight when BMI was between > 22 kg/m 2 and < 27 kg/m 2 , and as overweight with BMI ≥ 27 kg/m 2 (10).
To measure neck circumference (NC), the participants were in a full standing position, with the head positioned in the Frankfurt horizontal plane. An inelastic tape was placed at the midpoint of the neck. In men, the measurement was taken just below the laryngeal prominence. NC was considered high when men presented values ≥ 39 cm, and ≥ 35 cm for women (11). Waist circumference (WC) was measured with an inelastic measuring tape placed against the skin, at the midpoint between the iliac crest and the last rib at the end of the exhalation movement. The WC measure was considered according to gender, with cutoff points ≤ 90 cm for men and ≤ 80 cm for women (11).
The hip circumference (HC) cutoff value was ≤ 100 cm for both genders (11). The waist-to-height ratio (WHtR) showed a cutoff value of 0.5 for both genders. With regard to the waist-tohip ratio (WHR), the cutoff points were 0.8 for women and 1.0 for men (11). Regarding the body adiposity index (BAI), the values considered were 25 % for men and 35 % for women (12). Thigh circumference (ThC) was measured with an inelastic measuring tape, at the midpoint between the inguinal crease and the proximal edge of the patella, and the cutoff values were ≥ 44 cm for men and ≥ 43.70 cm for women (12).
To be considered hypertensive, the participants should have blood pressure values over 139/89 mmHg, according to the VII Brazilian Guideline on Arterial Hypertension. Below this value, they were classified as normotensive (13).
The laboratory data corresponded to the values established by the Brazilian Diabetes Society (14) and by the VI Brazilian Guideline on the Prevention of Dyslipidemias and Atherosclerosis (15), with FBG (≤ 100 mg/dL), HbA1c (< 7 %), TC (≤ 90 mg/dL), TG (≤ 150 mg/dL), LDL (≤ 100 mg/dL) and HDL (≥ 40 mg/dL). 10 mL blood samples were collected after 12 to 14 hours of fasting. The samples were centrifuged at room temperature, at 3000 rpm for 10 minutes, to separate the serum from the blood cells. FBG, TG, TC, LDL, HDL, and HbA1c were determined by the enzymatic colorimetric method with commercially available kits (Pars Azmun Co., Tehran, Iran) in an automated analyzer (Abbott, Alcyon 300 model, Abbott Park, IL, USA).
In this study, the participants in the experimental group received 60 capsules of 600 mg/each, with ginger (Zingiber officinale). The CG participants received 60 capsules of 600 mg/each, with microcrystalline cellulose (placebo). All the participants were instructed to take two capsules a day, one 30 minutes before breakfast and another 30 minutes before dinner, daily, for 30 days. Both the ginger and the placebo were encapsulated and packaged in identical, opaque white plastic vials, properly sealed. Each vial was numbered, and the dosage and the participant's name were printed on its label. The experiment participants were carefully instructed to avoid changes in their physical activity routines or eating patterns during the study period.
All the participants were instructed to return after the 30 days of intervention. In addition to that, guidelines were given on the continuity of ingestion of medications for T2DM, prescribed by the physicians, and on the usual care for managing the disease. Although foreign studies prove a safety ginger dose of up to 6 g/day, in Brazil, the maximum dosages allowed in compounding pharmacies for daily consumption are 2 g for fresh ginger and 1.2 g for 0.1 % ginger dry extract. Thus, ginger dry extract was selected, in which the daily dose was distributed in two 600 mg capsules instead of fresh ginger, which would have its daily dose divided into four capsules.
For production of the ginger capsules, the rhizome was used, processed in the form of powder, and the final product was 0.1 % ginger dry extract. In addition to that, an extraction was performed with water as solvent and starch as excipient. Drying was done by spray dryer. As for the physical aspects, the concentration of the extract in water was 33.51 %, and alcohol, 0.89 %. Dosage was 0.36 % for total gingerols (6-gingerol, 10-gingerol, 6-shogaol). In addition to the physical-chemical test carried out by the manufacturer, a microbiological test was performed, with values within normality for the amount of bacteria, fungi and yeasts, and the purity test measured heavy metals such as lead, copper, and antimony.
The use of ginger is authorized in Brazil and does not require permission to be used in research studies. Therefore, the concept of "Access to the Genetic Heritage" available in Provisional Measure 2,186-16/2001 does not apply. It is worth remembering that this spice, despite being originally from the island of Java, Indonesia, is widely used in the tropical regions of the world.
After the purchase of 0.1 % ginger dry powdered extract by Gemini Indústria de Insumos Farmacêuticos Ltda, the weighing, encapsulation, and repetition of the quality control tests, such as the physical-chemical test, were carried out in a compounding pharmacy that has the green seal of quality, the seal of excellence in franchising, and the Sinamm Diploma. Weighing was computed using an analytical balance. The ginger and placebo capsules were prepared by a private laboratory, certified by the National Health Surveillance Agency, in compliance with the international standards for handling products and medications. After preparation, the capsules were analyzed by pharmacists associated with the Federal University of Piauí, through biochemical and toxicological tests. The primary outcome was the reduction in the levels of FBG and CBG. The reduction in the lipid and anthropometric levels was established as the secondary outcome.

Data analysis and treatment
The data were analyzed by intention to treat, by repeating the values of the last evaluation, according to the CONSORT recommendations. The confounding variables were minimized through randomization in parallel groups (1:1). For the scalar variables, data was presented as mean and standard deviation or as median, minimum, and maximum. In the categorical variables, data was presented in the form of frequency and prevalence rate, in order to investigate associations between risk factors and disease. The Mann-Whitney's U test was used to analyze the characteristics of the groups. To verify the behavior of the numerical variables, at both moments, the Wilcoxon test was used. A significance level of 5 % was adopted. Pearson's chi-square test or Fisher's exact test for categorical variables were used to investigate the association between the variables. The statistical analyses were performed with the Statistical Package for the Social Sciences software, version 22.0 (United States) and the R program, version 3.3.1.

Results
A total of 24 participants received guidelines on the study, signed the FICF and were randomized, with 12 being allocated to the EG and the CG each. Subsequently, three EG participants were discontinued for the following reasons: two for travel reasons and one for reporting tachycardia. Thus, 21 individuals concluded the study (Figure 1).
Most of the patients were female (66.7 %), brown-skinned (66.7 %), and with a mean age of 57.9 years old (SD ± 9.22). The overall mean schooling of the participants was 6.95 years (SD ± 5.1) and 85.7 % lived with a partner or family members. One third of the participants stated being unemployed, received unemployment benefits or had the income of another family member, where 85.8 % had a monthly income of one to three minimum wages (value of the monthly minimum wage effective in 2017 in Brazil), and 85.7 % were married or in a stable union.
When asked about hyperglycemia or hypoglycemia episodes in the 30 days prior to the intervention, 66.7 % of the participants reported episodes of hyperglycemia and none of hypoglycemia. Almost half of the individuals (47.6 %) reported going to nursing and medical appointments every six months, and a large propor- In this study, arterial hypertension was the disease most associated with T2DM (61.9 %). Of the research participants, only one reported heartburn as an adverse effect.
In Table 1, it can be seen that, after the intervention with ginger, the researchers did not identify significant differences in the percentage values of the variables analyzed.  Table 2).  Source: Own elaboration.

Discussion
The results of this study showed that the daily intake of 1.2 g of ginger reduced weight, BMI, WC and LDL in 30 days of followup. Studies that used ginger in people with T2DM, with a focus on reducing blood sugar levels, also found positive results in reducing the anthropometric levels (weight, BMI and WC) (16)(17)(18)(19). Although directly linked to the diagnosis of T2DM, changes in the anthropometric levels -caused by the accumulation of fat -are still poorly investigated in studies that address the use of ginger.
In this research, although ginger has improved the lipid profile ranges, such as LDL (112.14-108.27 mg/dL, p = 0.038) and HDL (34.08-42.53 mg/dL, p = 0.086), there was no unanimity in the consistency of the individual results. A similar study, involving 80 people with T2DM, with 41 using 3 g/day of ginger, for eight weeks, concluded that the product reduces LDL levels and increases HDL levels (17). Iranian researchers conducted a clinical trial with 64 patients for two months, in which the participants used 2 g/day of ginger and achieved a reduction in the mean LDL values (77.33-65.73 mg/dL, p = 0.04). However, when analyzing the impact on HDL, the results were negative, as the levels of this cholesterol decreased (42.53-38.66 mg/dL, p = 0.28) (16). Amounts of ginger smaller than these have not been shown to be effective in reducing the lipid levels (20).
Results like these are important, since it is already firmly established in the literature that insulin resistance in the peripheral tissues is intimately associated to the high amount of circulating lipids and to the accumulation of tissue lipids, which indicates a high need for control, essential to minimize secondary complications of T2DM and of associated diseases (21). Ginger has enzymes that inhibit the metabolism of carbohydrates, preventing hyperglycemia or the perpetuation of insulin resistance, and appears to modulate the action of insulin while regulating blood glucose homeostasis (21).
Although the results did not show that fasting blood glucose or capillary blood glucose were reduced after the intervention, different studies highlight the hypoglycemic effect of ginger in non-insulin-dependent T2DM patients (17)(18)(22)(23)(24)(25)(26)(27). The outcomes of this study and others with a similar objective can be supported by differences in the patients' responses, the duration of the disease, the dose, the intervention time or because of the type of therapeutic regimen. In general, all this evidence shows that the consumption of a moderate dose of ginger can modify the glycemic and lipid status, and reduce the anthropometric parameters of people with diabetes, pointing out the value of the product in the management of the disease. Thus, it is possible to say that ginger can even be used as an adjunct, but not exclusive, therapy for the control of T2DM. In addition to that, it is important to note that ginger is a low-cost product, easily found and with great potential to be introduced into the daily lives of people with T2DM and comorbidities associated with lipid alteration.
Undoubtedly, the results of research studies like this support the health team in the use of products like ginger in the clinical practice, increasing the management power of people with T2DM, especially in primary care. Likewise, it is also necessary to take into account that the current scenario requires greater autonomy, preparation and leadership from these professionals in the creation of policies that disseminate effective and innovative practices, as highlighted by the Nursing Now campaign (28)(29)(30).
Based on our observations and on data from other research studies, it is possible that ginger is considered a promising supplement for T2DM therapy when hypertriglyceridemia and hyperlipidemia cannot be satisfactorily controlled by means of other strategies, such as exercise, diet and prescription medications. A research study on the cost-effectiveness of the product is also important, since the use of ginger can be part of the economic and health strategies used by the Brazilian government to control T2DM.

Study limitations
As a limitation of this pilot study we point out the intervention time, of only 30 days, which seems to be short to show metabolic changes in patients with diabetes, as well as the sample size, precluding data generalization. Another limitation of the research was the therapeutic dose of only 1.2 g per day -the maximum dose allowed by the Brazilian government. In addition to that, the need to monitor and record the dietary pattern and the practice of physical exercises by the participants is emphasized, since they can influence the outcomes found.

Conclusions
This study identified that ginger, in doses of 1.2 g/day, for 30 days, can help to reduce some anthropometric and lipid levels in people with T2DM, but it does not have enough hypoglycemic power to reduce the investigated glycemic levels. In addition to that, inconsistencies found in the literature, with positive and negative results in studies of this nature, raise the need for further research studies. Therefore, caution is required when using the results. Nurses must lead research studies like this, as they are at the forefront of care for people with T2DM, especially in primary care. In addition, policy makers are expected to expand the list of recommendations for this product and to provide opportunities for developing new studies that take into account the limiting aspects of this research, especially the size of the daily therapeutic dose.
Conflict of interests: None declared.