INTRODUCTION

Type 2 Diabetes Mellitus (T2DM) can be characterized as a metabolic and multifactorial dysfunction, which demands continuous care. In the last two decades, the disease has increased from 151 million to 463 million cases worldwide, among people aged 20 to 79 years⁽¹⁾. In Brazil, almost 20 million peop= le live with the disease, with the country in fifth place in the ranking of th= ose with the highest number of cases, and in third of those who spend the most = on the disease^(1-2). Once poorly controlled, diabetes has severe implications for the patient who has the disease, such as micro and macrova= scular changes, reduced quality of life, frequent hospitalizations and premature d= eath⁽¹⁾.

Despite effort= s to control this disease, factors such as clinical stagnation and low acceptanc= e to the treatment, bring complications that further reinforce the degree of chronicity of the disease, leading to a greater need for care^{(1-3).
The patient with diabetes also has, in most cases, another correlated disea=
se,
arterial hypertension. An explanation for the appearance of these comorbidi=
ties
is due to the increase in peripheral arterial resistance, caused by vascular
remodeling and an increase in the volume of body fluid associated with
hyperinsulinemia and hyperglycemia induced by insulin resistance^{(4).
Deregulation of arterial hypertension among Brazilians is among the main ca=
uses
of premature deaths registered by the public health system.}}

Alternatives to mitigate recurrent problems related to diseases like these, have been outli= ned by the Brazilian government, which in recent years has maximized the use of= the so-called Complementary and Integrative Medicine (CAM). Such practices invo= lve natural mechanisms, using safe and effective products and techniques, in addition to contemplating a patient-focused approach. Its insertion in Prim= ary Health Care has gained strength not only due to the countless evidences it = presents, but also due to the cost, quality, versatility and variety of resources they have in the management of chronic diseases^(5-6).

Among the CAMs= available and regulated in the national territory, one stands out for the wide range = of products and applications, phytotherapy. Phytotherapy has been used in heal= th promotion and in the treatment of acute and chronic diseases, through the u= se of medicinal plants in their different pharmaceutical forms⁽⁷⁾. =

In this scenar= io, Brazil stands out for having the greatest plant diversity in the world, gre= at empirical application of culturally established medicinal plants and techno= logy to scientifically validate this knowledge. Particularly for the treatment of T2DM, researchers have shown that ginger (Zingiber officinale) can b= e a potential supporting factor in reducing glycemic, lipid and even blood pres= sure levels in this population^(8-9).

However, the literature is not unanimous and research on the use of this herbal medicine= to reduce blood pressure in people with T2DM is still scarce. Furthermore, to date, no studies of this nature have been identified in the country. Also, = the lack of records on the application of herbal medicines like this reflects directly on the clinical practice of nurses, since further clarifications a= re still needed to legitimize interventions with natural products. =

One of the main reasons for the development of this analysis was based on the practical experience of nursing in Basic Health Units linked to Primary Health Care in Brazil. We realized that our patients had high blood pressure values and reported, as well as the need to lower blood glucose, minimize blood pressure values.

The associated problems, forming a cardiometabolic disorder common among patients with Diabetes, cause the risks of complications to accelerate and become more common, spreading a high burden on health systems. Because we have a free public health system, with a population lacking in economic resources, it is imperative to investigate more about the subject. Therefore, the objective = of this study was to evaluate the effectiveness of ginger in reducing blood pressure levels in patients with T2DM.

METHODS

Study design

Randomized, double-blind, placebo-controlled and parallel group clinical trial.

Location, participants and eligibility criteria

The study was carried out in seven Basic Health Units (BHU) in the city of Picos, in the region of Vale do Rio Guaribas, in the interior of the state of Piauí, Brazil. = The population consisted of people diagnosed with T2DM and associated arterial hypertension, registered and followed up at the BHU where the data were collected. The BHU were chosen at random, through a draw. Units that were operating at least in the morning and afternoon shifts and had people registered and followed up with T2DM diagnoses participated in the draw.

We included pe= ople diagnosed with T2DM for at least two years, aged between 20 and 80 years, w= ith preserved cognitive functions - according to the Mini Mental State Examinat= ion (MMSE), being treated with oral antidiabetics and = glycated hemoglobin (HbA1c) between 6.0% and 10.0% at baseline. The cut-off point established for HbA1c is justified because, with values below 6.0%, people with T2DM already have a good control of this biomarker; and a= bove 10.0%, these already had important deregulations, making the application of= the research unfeasible⁽²⁾.

The exclusion criteria used were people using alcohol or tobacco, using any natural produ= ct to control diabetes, on insulin therapy, with the presence of chronic chang= es (cardiovascular, liver, kidney, gastric or mental disorders diagnosed), pregnant women or lactating women. Chronic changes and mental disorder were assessed using information provided by the individuals themselves. People c= ould be discontinued from the study if they experienced any adverse events. The assessment of blood pressure levels was established as a secondary outcome = of the research. No cut-off points were established for blood pressure values.=

In the city wh= ere the research was carried out, there were no records on the number of people with DM2 and HbA1c values between 6.0% and 10.0%, monitored a= t BHU. Thus, the sample was calculated using the average difference between two gr= oups using the G*Power 3.1.9.2 software, in which a significance level of 5% and= a test power of 80% were fixed, based on a previous study⁽¹⁰⁾, totaling 102 people, 51 for each group. However, when considering possible losses, a percentage of 20% was added, totaling 124 people, 62 people for e= ach group.

Data collection

Data collection was carried out from December 2017 to March 2018. In total, 229 people were recruited, and of these, 85 were excluded for the following reasons: 24 did= not have HbA1c between 6.0% and 10.0%; 15 used alcohol; 11 did not use oral antidiabetics; 10 used tobacco; nine used insulin; nine had severe cardiovascular problems, and seven had some kidney deficiency.

For recruitmen= t, a previously trained team held meetings with the health professionals of each= BHU to explain the objective of the study. Invitation letters and the Free and Informed Consent Term (ICF) were given to community health agents so that t= hey could pass it on to potential research participants, giving them time to re= ad and ask questions about the research. The ICF was only signed after confirm= ing the interest of each of the recruits.

Randomization = was created by software and stratified by BHU, with a 1:1 allocation in parallel groups, using random block sizes of six people, based on the HbA1c values. = Each person was indicated to participate in a group based on chance, with an equ= al chance of being allocated to one of the comparison groups.

The allocation sequence was performed by two members of the research group who did not participate directly in the data collection. These were responsible for randomizing the participants into blocks, preparing the bottles, and number= ing them. Thus, the principal investigator and the participants were blinded du= ring the intervention. For randomization, a numerical list was generated, where = the sequence of even numbers corresponded to the Experimental Group (EG), and t= he sequence of odd numbers to the Control Group (CG). The group in which each person was part was only revealed to the main researcher after analyzing the data.

At the EG, each participant received a bottle containing 60 capsules of ginger (Zingiber officinale), per month, for three months. Each capsule contained 600 mg= of powdered ginger. In the CG, the participants received a bottle containing 60 placebo capsules (microcrystalline cellulose), per month, for three months.= Each capsule contained 600 mg of microcrystalline cellulose. Both the GE and the= GC were instructed to take two capsules a day, one 30 minutes before breakfast= and the other 30 minutes before lunch.

Both the capsu= les and the ginger and placebo bottles were the same, to avoid contamination of= the investigated, and contained a label with information about the dosage, expiration date of the product and the return date. Each bottle was numbere= d to facilitate the process of randomization of participants. Within 25 to 29 da= ys a new bottle was delivered. Telephone calls were made to remind participants = to look for a new bottle at the BHU in which they were accompanied.=

The ginger was processed in powder form and the final product was the 0.1% dry extract. To obtain the raw material, an extraction was performed with water as a solvent and starch as an excipient. The drying was done by spray dryer. The concentration of the extract in water was 33.51% and alcohol 0.89%. The dos= age was 0.36% for total gingerols (6-gingerol, 10-gingerol, 6-shogaol). In addi= tion to the physical-chemical test carried out by the manufacturer, the microbiological test and the purity test with heavy metal count were perfor= med. In Brazil, ginger is authorized for use and makes up research exempt from authorization. Both the ginger and the placebo were prepared by a private laboratory, certified by the National Health Surveillance Agency (ANVISA), = in accordance with national regulations for drug preparation.

In both groups, participants were encouraged to continue taking routine diabetes medications and to maintain the same eating and exercise habits. In addition, the participants were aware that they could leave the research at any time and = for any reason, without prejudice to the health treatment offered by BHU. All t= his information was extended to the participants' family and/or caregivers.

The collection= was divided into two stages. In the first, the participants received instructio= ns about the study and had collected socioeconomic, clinical, and laboratory d= ata. It is noteworthy that, for this study, laboratory data were not considered = in the analyzes. For data collection, a questionnaire was used containing socioeconomic variables (age, skin color, gender, education level, work activity, income, socioeconomic status, marital status, and who lives with)= and clinical variables (mean values of systolic blood pressure and diastolic, time of diagnosis with T2DM, presence of hypertension, frequency= of follow-up at the BHU and physical exercise). As they were self-reported, the information provided during data collection at the BHU could have a response bias.

Blood pressure (BP) was measured three times, to establish the mean value, before the beginning of the intervention, and after 90 days, at the end of the intervention. The reference values used are by the VII Brazil= ian Guideline for Hypertension⁽¹¹⁾. To the absent participants, a telephone call or home visit was made to recruit them and schedule new date= s for participation. During the follow-up period, participants received a telepho= ne call per month to remind them of the importance of medication adherence, as well as, so that the main researcher could register adverse events. Three months after the delivery of the first bottle containing ginger capsules or placebo, the participants had clinics collected again.

In this resear= ch, 142 were randomized, 72 in the EG and 72 in the CG. However, only 103 people completed the entire treatment (Figure 1). The reason for the losses was li= nked to factors of discontinuity, outlier or adherence to intervention below 80%= - assessed by the Morisky Test. The adverse events presented were diarrhea (n =3D 01) and gastrointestinal discomfort (n =3D 0= 1).

Table 1 – Characterization of participants accor= ding to clinical variables.

Variables	Total (n=3D 103)	Control Group (n=3D 56)	Experimental Group (n=3D 47)	*p-value*
T2DM time
2 to 5 years	42 (40.8%)	22 (39.3%)	20 (42.6%)
6 to 10 years	33 (32.0%)	20 (35.7%)	13 (27.7%)	0.670^*<= /sup>
> 10 years	28 (27.2%)	14 (25.0%)	14 (29.8%)
Hypertension
Yes	62 (60.2%)	31 (55.4%)	31 (66%)	0.274^*<= /sup>
Not	41 (39.8%)	25 (44.6%)	16 (34%)
Follow-up frequency at BHU=
Monthly	18 (17.5%)	09 (16.1%)	09 (19.1%)
Quarterly	45 (43.7%)	28 (50.0%)	17 (36.2%)
Semester	26 (25.2%)	12 (21.4%)	14 (29.8%)	0.558^*<= /sup>
Yearly	14 (13.6%)	07 (12.5%)	07 (14.9%)
Physical exercise			<= /o:p>	<= /o:p>
Before the intervention	38 (35.9%)	21 (37.5%)	17 (36.2%)	0.889^**=
After the intervention	35 (34.0%)	19 (33.9%)	16 (34.0%)	0.990^**=

Source: Resear= ch data, 2018.

* Pearson's Chi-square test; ** Chi-square test. 95% confidence interval.

DISCUSSION

The results of this study showed that the use of ginger, in doses of= 1.2 g per day, did not reduce blood pressure values in individuals with T2DM. Although most participants were also diagnosed with high blood pressure, and used antihypertensive medications, the herbal medicine did not have enough effect to be indicated as adjuvant therapy.

In our research, there was a higher prevalence of females. Women hav= e a high tendency to accumulate fat, generating pro-inflammatory changes, insul= in resistance and, consequently, diabetes⁽¹²⁾. The average age among the participants was 58 years. Evidence has shown that during the aging process, people with diabetes have continuous exposure to = hyperglycemia, which can lead to systematic endotheli= al dysfunction and cardiovascular complications and interfere with blood gluco= se and blood pressure control⁽^13).

As for the marital situation, we identified a predominance of married people living with the family. Compared to single people, marriage offers an environment of continuous and lasting support, which can promote physical a= nd mental health. Also, frequent contact with family and friends is associated with positive self-care behaviors and adherence= to treatment⁽¹⁴⁾.=

In this study, more than half of those investigated were retired and= had an income below the minimum wage. The etiology = of chronic diseases such as T2DM or hypertension, is strongly associated with inappropriate lifestyle habits and stressors resulting from work activity or unemployment. In addition, when poorly controlled, diabetes brings substant= ial costs to those who have the disease, making care for those with low income = unfeasible⁽³⁾.

Linked to this is the time of diagnosis of the disease. In this surv= ey, more than 40% of the participants had less than five years of diabetes. This fact may be associated with less knowledge about the disease and, consequen= tly, insufficient control of the disease and related comorbidities, such as hypertension⁽¹²⁾. Hypertension w= as present in more than 60% of the individuals in both groups analyzed (EG and CG), which led us to assess whether ginger had any effect on this variable.

After the intervention, it is possible to observe a tendency of reduction in the values of systolic and diastolic pressure of= the participants who used ginger, although not significant, not allowing the indication of the therapy. Similar outcomes have also been found in clinical trials developed in other countries⁽<= sup>9,15). Corroborating the findings, a systematic review that investigated the effec= t of different herbal medicines used for therapeutic purposes did not identify antihypertensive components in ginger⁽⁷⁾.

However, the literature is not unanimous, and a study who researched= the effect of ginger powder supplementation on blood pressure in patients with = DM2, observed a significant decrease in blood pressure systolic and diastolic, as well as the pulse pressure and average BP, indicating that daily consumptio= n of 3 g capsules ginger powder for 8 weeks brings improvements to blood pressur= e in patients with DM2⁽⁸⁾.

In this perspective, a systematic review with meta-analysis pointed = out that supplementation with ginger presents favorable results in blood pressu= re, being able to reduce systolic and diastolic BP with significance only in investigations with individuals aged ≤50 years, with 8 ≤ weeks = of research and doses of ginger ≥3 g daily⁽¹⁶⁾.

This hypotensive effect of ginger may be related to its ability to inhibit the Angiotensin-1-converting Enzyme (ACE), potent vasodilator that plays an important role in the development of hypertension⁽¹⁷⁾. Thus, being considered a new angiotensin II type 1 receptor antagonist, it inhibits ACE by lowering blood pressure. In addition, it may also be associ= ated with platelet hyperactivity and potential neuroprotective effects^(17-1=
8).

Ginger can still be used in an associated with antihypertensive drug= s, playing an adjunct role in the treatment of hypertension, providing an additional effect⁽¹⁸⁾. However, such results present us with a still limited scenario, which does not allow to expand discussions on the subject and point to the need for further investigations in the area.

In this context, Nursing in Advanced Practices has shown great poten= tial for the treatment of people with chronic diseases by all the innovative practices introduced in recent years⁽¹⁹⁾. Being at the forefront = of care for chronic patients, nurses must assume leadership roles and use rese= arch such as this to maximize clinical performance in places such as Primary Hea= lth Care, through comprehensive and resolving interventions= ⁽²⁰⁾.

This study is unprecedented in the country and sought to fill gaps in the literature about the role of ginger in reducing blood pressure in people with T2DM. Although without statistically positive outcomes, this clinical trial can increase the knowledge of health professionals about the use of t= his CAM in the management of diseases such as diabetes.

We consider that our research had as main limitations the interventi= on time and the dose of ginger offered. Despite the fact that most of the exis= ting research on the subject has carried out interventions for 90 days, we belie= ve that a longer follow-up period would allow a better assessment of the outco= me drawn. As adverse events, one participant in the CG and another in the EG experienced episodes of nausea and diarrhea, respectively.

CONCLUSION

The results of this study show that ginger, at doses of 1.2 g/day, d= id not have the potential to reduce blood pressure in people with T2DM. It is suggested that future investigations expand the dose and the intervention period and explore the cost-effectiveness of the herbal medicine to subsidi= ze its insertion in the Brazilian health system.

Regarding nursing practice, health promotion strategies are essential for the prevention of chronic diseases. In this context, advanced disease maintenance and control practices, such as those in this study, are necessa= ry for successful care science. The findings suggest that nursing professionals should take up research in order to increase the scope of resources to be i= ncluded in their care plan, as well as in investigating tools to prevent or slow the advance of diseases such as diabetes and hypertension.

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Submission: 2022-01-31

Approval: 2022-02-08

Variable	Control Group (n=3D 56)	Experimental Group (n=3D 47)	*p-value*
Systolic blood pressure	=	=
Before the intervention	125 ± 15.93	131 ± 19.99	= 0.146^*
After the intervention	125 ± 14.36	130 ± 18.69	= 0.147^*
p	0.527^**<= /o:p>	0.870^**<= /o:p>
Diastolic blood pressure	=	=
Before the intervention	77 ± 08.90	80 ± 09.47	0= .039^*
After the intervention	76 ± 09.44	76 ± 14.77	0= .937^*
p	0.955^**<= /o:p>	0.066^**<= /o:p>