Clinical trial NCT03416127
Conditions: Diabetes Mellitus, Type 2
Keywords: Diabetes Mellitus type 2 Glycemic control Propolis Metformin Pharmacological treatment-naïve patients
Sponsor: University of Guadalajara
Start date: 2018-01-30; Completion date: 2019-12-20
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The aim of this study was to evaluate the effect of propolis or metformin on glycemic control in patients with type 2 diabetes mellitus without pharmacological treatment.

All patients received for 12 weeks propolis, metformin or placebo. Fasting serum glucose, 2-h serum glucose after oral glucose tolerance test, glycated hemoglobin A1c, a metabolic profile, areas under the curve of glucose and insulin, insulinogenic index, Stumvoll index, and Matsuda index were measured.

Detailed description:
A randomized, double-blind, placebo-controlled clinical trial of three pharmacological groups was carried out, with the participation of 36 patients with type 2 Diabetes Mellitus without pharmacological treatment.

At the beginning and end of the study, fasting serum glucose, 2-h serum glucose after oral glucose tolerance test, glycated hemoglobin A1c, and a metabolic profile were measured. Areas under the curve of glucose and insulin, total insulin secretion insulinogenic index), the first phase of insulin secretion (Stumvoll index), and insulin sensitivity (Matsuda index) were calculated.

All patients received for 12 weeks two capsules a day, one before the first bite of breakfast and another before the first bite of dinner. 12 of them took propolis (300 mg), another 12 received metformin (850 mg), and 12 more placebo in the same pharmacological presentation.

This protocol was approved by a local ethics committee and written informed consent was obtained from all volunteers.

Results are presented as mean and standard deviation. Intra-group differences were evaluated using Kruskal-Wallis and Mann-Whitney U-tests, while inter-group differences were calculated with the Wilcoxon test; p≤0.05 was considered significant.

Arms: arm 1: Propolis capsules, 300 mg, two times per day before break-fast and dinner during 12 weeks. arm 2: Metformin capsules, 850 mg, two times per day before break-fast and dinner during 12 weeks. arm 3: Placebo capsules, two times per day before break-fast and dinner during 12 weeks.
Interventions: intervention 1: Propolis intervention 2: Metformin intervention 3: Placebo
Intervention descriptions: intervention 1: Propolis capsules, 300 mg, two times per day before break-fast and dinner during 12 weeks. intervention 2: Metformin capsules, 850 mg, two times per day before break-fast and dinner during 12 weeks. intervention 3: Calcined magnesium, two times per day before break-fast and dinner during 12 weeks.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
“Effect of Propolis or Metformin Administration 
on Glycemic Control in Patients With Type 2 
Diabetes Mellitus” 
 
NCT03416127 
 
April 6, 2017 
 


Effect of Propolis or Metformin Administration on Glycemic Control in 
Patients With Type 2 Diabetes Mellitus 
 
INTRODUCTION 
Type 2 Diabetes Mellitus (DM2) is a health problem that has reached alarming levels, as 
currently, about half a billion people suffer from it around the world. For 2019, a total of 463 
million was estimated and an increase of 51% is expected by 2040.1 It is a disease 
characterized by dysfunction of beta cells, hepatic glucose metabolism and peripheral insulin 
resistance, a state in which tissues sensitive to it show a decreased response to normal insulin 
levels.2  
The first-line treatment in newly diagnosed patients is metformin, mainly due to its efficacy 
in reducing glycemic control, safety profile, and weight neutrality.3,4 However, this depends 
on factors such as treatment compliance, access to medicines, counseling, regular monitoring 
of blood sugar levels, access to health care services, and quality of management. To date, a 
significant number of people around the world use complementary and alternative medicine 
(CAM) to treat chronic diseases, with reports of 64%. Of these, 35.5% use CAM for DM2.5 
Propolis, is a natural product produced by the bee Apis mellifera by adding salivary secretions 
(β-amylase) and wax to the balsamic resinous material, which they collect from shoots, 
exudates of trees and other parts of the plants as lipophilic materials in the leaves, mucilages, 
gums, resins, latex, etc. Etymologically the term propolis, comes from the Greek and means 
in “defense of the city (or beehive)”.6–9 It has been known and used since ancient times by 
offering options such as antimicrobial, anti-inflammatory, antioxidant, antitumor, antiulcer, 
anesthetic, hepatoprotective and healing therapy.6,10,11 It is composed of flavonoids, terpenes, 
phenolic acids, as well as proteins, sugars, vitamins and abundant minerals.10,11 
Recent studies have shown the efficacy of propolis on the reduction of fasting glucose and 
glycated hemoglobin,9,12,13 insulin resistance13,14 and postprandial glucose.14 However, there 
is a controversy between some results, as Fukuda et al. indicated that there was no significant 
difference in the parameters of glycemic control and insulin resistance.15 Likewise, Zakerkish 
et al. found no relevant reduction in fasting glucose after propolis supplementation.14 


Therefore, there is a need for further studies, as there is no evidence from studies evaluating 
the effect of propolis on glycemic control in newly diagnosed patients without drug 
treatment. In addition to this, it has not been compared to the gold standard, metformin. Our 
hypothesis is that the administration of propolis or metformin modifies glycemic control in 
newly diagnosed patients without pharmacological treatment. The objective of this study is 
to evaluate the effect of propolis or metformin administration on glycemic control in recently 
diagnosed patients without pharmacological treatment. 
 
MATERIAL AND METHODS 
Selection criteria 
Patients with a diagnosis of DM2 less than 5 years old and without pharmacological treatment 
for at least 3 months before entering the study, 30 to 60 years of age, mild to moderate 
physical activity, stable body weight for at least 3 months before the study, body mass index 
(BMI) of 25.0 to 34.9 kg/m2, fasting serum glucose <13.88 mmol/L and postload serum 
glucose >11.10 mmol/L, will be criteria for entering the study. For the selection of individuals 
diabetes detection campaigns will be carried out in the metropolitan area of the City of 
Guadalajara. Women in the reproductive stage at risk of pregnancy, subjects who consumed 
drugs or supplements that modify the behavior of DM2, personal history of cardiovascular, 
kidney, pancreatic or thyroid disease and/or uncontrolled systemic arterial hypertension, 
known allergies to bee’s sting or its derivative products, intolerance to metformin, total 
cholesterol (TC) ≥6.20 mmol/L, triglycerides (TG) ≥4.48 mmol/L will be excluded. 
Individuals with lack of tolerability to propolis, metformin and/or placebo, with adherence 
to treatment <80%, in the presence of a serious adverse event and/or who withdrew informed 
consent will be eliminated. 
 
Study design 
A randomized, double-blind, placebo-controlled clinical trial of three pharmacological 
groups will be carried out, with the participation of 34 patients with a recent diagnosis of 
DM2 according to the criteria of the American Diabetes Association.16 The propolis capsules 


will be obtained from NOW® of Chicago, Illinois (USA), containing 300 mg of propolis 
powder. Calcined magnesia will be used for the placebo. The allocation will be done by 
simple randomization using a list of numbers. All patients will receive for 12 weeks one 
capsule before the first bite of breakfast and another before the first bite of dinner. 12 of them 
took propolis (300 mg twice a day), another 12 received metformin (850 mg twice a day) and 
12 more, placebo in the same pharmacological presentation. Each participant will receive 
medical nutritional therapy and will be instructed to continue with their normal physical 
activity. 
 
Clinical and laboratory measurements 
The medical history of each patient will be taken and anthropometric indices will be 
measured that included: height, weight, BMI, waist circumference (WC) and percentage of 
fat mass. In addition to blood pressure. Five visits will be completed during the study and a 
2-h oral glucose tolerance test (OGTT) will be performed at the beginning and end of the 
intervention to calculate the areas under the curve (AUC) of glucose and insulin, total insulin 
secretion (insulinogenic index), first phase of insulin secretion (Stumvoll index) and insulin 
sensitivity (Matsuda index). For this, the individuals will take a solution with 75 g of 
anhydrous glucose dissolved in 300 ml of water in 5 minutes. After that, blood samples will 
be taken through a heparinized catheter before and at 30-min intervals (30, 60, 90 and 120 
minutes) for 2 hours. At each visit, the presence of adverse events will be verified through 
the diary and compliance through the capsule count. 
Laboratory tests will be performed at 8:00 a.m. after an overnight fast from 10 to 12 h. Body 
weight will be evaluated by bioimpedance with a digital scale (Tanita®), with the participant 
in a standing position and wearing light clothing, without footwear and with the bladder 
evacuated before the measurement. For height, subjects will be asked to remove their shoes 
and stand with their feet together; measurements will be rounded to the nearest centimeter. 
WC will be taken at the midpoint between the highest point of the iliac crest and the lowest 
rib on the midaxillary line to the nearest centimeter. Percentage of fat mass will be evaluated 
through bioimpedance. BMI will be calculated as weight (kg) divided by height (m2). A 
digital sphygmomanometer (Omron Hem-907 XL®) will be used to determine blood 


pressure, and the mean value of three measurements will be recorded after a 5-min rest 
period. 
Venous blood samples will be obtained and kept at room temperature for 30 min. The 
samples will be centrifuged and the serum will be placed in three aliquots; one will be used 
immediately for the measurement of fasting glucose, glycated hemoglobin A1c (A1C), TC, 
TG, high-density lipoprotein cholesterol (HDL-c), uric acid and creatinine, and the rest will 
be frozen at -20 °C for the determination of insulin. All biochemical measurements will be 
calculated with enzymatic colorimetric methods on an automatic analyzer (Erba XL-100®) 
with BioSystems S.A. reagents. Insulin concentrations will be measured with the enzyme-
linked immunosorbent assay (ELISA) technique using the kit (DRG, Inc). 
To calculate low-density cholesterol, the Friedewald formula will be used: LDL-c (mmol/L)= 
TC (mmol/L) - HDL-c (mmol/L) - [TG (mmol/L) / 2.2], while for very low density 
cholesterol (VLDL) the ratio of TG (mmol/L) / 2.2 will be used. With a liquid 
chromatography the percentage of A1C will be calculated. The AUC of glucose and insulin 
will be calculated with the polygonal formula. Total insulin secretion will be assessed with 
the insulin index: (∆AUC of insulin) / (∆AUC of glucose). With the Matsuda 10000 / √ 
([(Glucose 0^ '∙ Insulin 0 ^') (Average of the PTOG ∙ Average of the insulin in the PTOG)]) 
index the insulin sensitivity will be estimated, while with the index from Stumvoll 1283 + 
1.829 × insulin 30' - 138.7 x glucose 30’ + 3.772 × insulin 0', the first phase of insulin 
secretion. 
 
Sample size 
For this study, the sample size it’s calculated using a formula for mean difference17 with a 
statistical confidence of 95%, a statistical power of 80%, a standard deviation (SD) and an 
expected difference for fasting glucose, A1C and 2-h glucose of 0.6 mmol/L12 and 1.0 
mmol/L9,  0.5% and 0.8%12, 2.3 mmol/L18 and 3.9 mmol/L19, respectively. While for 
metformin it’s of 2.4 mmol/L20 and 3.0 mmol/L21, 1.0% and 1.5%22, 3.5 mmol/L23 and 5.5 
mmol/L24, respectively. A total of 12 patients is obtained for each group, including 20% of 
the expected loss. 


Security measures 
All patients will be informed about the possible adverse effects of propolis and metformin; 
they will have the emergency telephone numbers of the responsible and associated 
investigators. 
 
STATISTIC ANALYSIS 
The study will be designed to demonstrate the effect of propolis and metformin relative to 
placebo in terms of the outcome variables of effectiveness. Assuming there are no differences 
in propolis and metformin versus placebo regarding effectiveness in reducing glycemic 
control, it's calculated that approximately 36 randomized patients will provide ~80% power 
to demonstrate superiority. 
All statistical analyzes will be performed by intention to treat, which will be included 
randomized patients who receive at least 1 dose of study treatments and for whom there has 
a baseline value on measurements. First, with the Kruskal-Wallis test, it will be tested 
whether the baseline data group of primary and secondary variables come from the same 
population, that is, whether the 3 groups are comparable as no statistically significant 
differences are found. 
Then, using the Kruskal-Wallis test, the final data will be evaluated and with those that will 
be significant a post-hoc test (Mann Whitney U) will be performed, comparing propolis 
versus metformin, propolis versus placebo, and metformin versus placebo. Differences 
between baseline and final measurements for primary and secondary variables will be 
calculated with the Wilcoxon test. Statistical comparisons will be made using a comparative 
type 1 error of 5% (two-tailed). 
The safety profile analysis will include patients who receive at least 1 dose of study 
medication; safety data will be summarized using descriptive statistics. 
 
FINANCING 
The financing will be by own resources of the University of Guadalajara. 


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ICF_001.pdf: 
 
 
 
 
 
 
 
“Effect of Propolis or Metformin Administration 
on Glycemic Control in Patients With Type 2 
Diabetes Mellitus” 
 
NCT03416127 
 
April 6, 2017 
 


INFORMED CONSENT FORM 
“Effect of Propolis or Metformin Administration on Glycemic Control in Patients 
With Type 2 Diabetes Mellitus” 
 
The format may contain words or terms that you do not understand; please ask the doctor in 
charge of the study in your interview to explain in case this situation exists. Sign this 
informed consent form until all your doubts are satisfactorily clarified, and you are convinced 
that you want to participate in the study. 
 
Purpose of the study 
The purpose of the study is to evaluate the effect of the administration of propolis or 
metformin on glycemic control in patients with Type 2 Diabetes Mellitus without drug 
treatment, this due to the continuous growth in the incidence and prevalence rates of 
Diabetes, where glycemic control is by nature the protagonist of unleashing it. Currently, the 
first-line drug treatment in newly diagnosed patients is metformin, and although its effect to 
reduce hyperglycemia is well documented, both in monotherapy and in combination, there is 
a marked tendency to develop a progressive deterioration in glycemic control and 
abandonment of treatment, however, recent studies have shown that natural products play an 
important role as alternatives in the treatment of various diseases, mainly due to their low 
toxicity. Such is the case of propolis, a balsamic resinous material collected from shoots, 
exudates of trees and other parts of plants by the bee Apis mellifera, of which various studies 
in animal models and clinical trials have shown that it could be considered as an agent 
antidiabetic. 
The study will last 12 weeks, which includes 6 visits and the participation of 36 people who 
will receive: 
1) Metformin, an antidiabetic medicine. It will be taken 2 times a day, 1 capsule per dose, 1 
at breakfast and 1 at dinner, provided free of charge and in sufficient quantity during the three 
months of the study. 


2) Propolis, which is a capsule that when consumed has shown effects on Type 2 Diabetes 
Mellitus. It will be taken 2 times a day, in 1 capsule per dose, 1 at breakfast and 1 at dinner, 
being provided free of charge and in sufficient quantity during the three months of the study. 
3) Placebo that looks and looks like medicine but is not and therefore will have no effect on 
your weight, fat, blood glucose or blood pressure. The placebo is administered so that neither 
you nor the doctor evaluating the study know what medication you are taking, however, this 
information can be obtained if required. 
So we think you could be a good candidate to participate in this project. You and the rest of 
the study participants will take the treatment as directed and you will not know which group 
you will belong to. 
 
Procedures 
If you agree to participate, the following will take place: 
1. Procedures that are routine in the care of patients in this service: 
You will come here with us on a fast from at least 8 hours to 8:00 AM. 
a. Clinical Procedures: You will have a medical history that includes a complete 
physical exam with the measurement of your blood pressure, weight, height and 
waist. 
b. Laboratory procedures: we will take a venous blood sample (approximately 2 
teaspoons of your blood), from one of your arms to perform some laboratory studies, 
then you will be given a drink containing 75 grams of glucose diluted in 300 ml of 
water, to measure your blood glucose after an oral glucose load and thus determine 
if you are intolerant to it. In addition, the laboratory studies that we will perform 
include the measurement of your fasting glucose level, creatinine, glycated 
hemoglobin A1c and a lipid profile. For your safety and hygiene, all the material 
used in this study is sterile and disposable, and at the end of the planned analyzes, 
the rest of the sample will be destroyed. 
 


The purpose of conducting clinical and laboratory studies is to learn more about your general 
health conditions and glucose levels both fasting and 2 hours after a 75g glucose load. It will 
take us approximately 2 hours to perform these clinical and laboratory tests. We will give 
you the results of your lab studies within 3 days. 
Once this letter of consent has been signed and if the criteria to enter the study are met, 
another day of fasting of at least 8 hours will be scheduled at 8:00 AM where the following 
specific procedures will be performed: 
2. Specific procedures for this investigation: 
a. Nutrition counseling will be provided by trained staff. 
b. Laboratory tests will be taken at the first visit and at the end of the study to compare 
the glucose and hemoglobin A1c levels you had on admission with those you had on 
your exit from the study. 
c. The visits with us will be monthly, and within them, we will take your height, weight, 
waist circumference and blood pressure to observe the evolution you have had with 
the medicine. You will also be asked if the capsules have been taken every day, if 
there has been a lack of taking at any time, as well as the possible adverse effects with 
the treatment. 
d. After 3 months of administration of the assigned drug, you will be cited again with a 
fast of at least 8 h at 8:00 AM and the clinical measurements will be taken at the 
beginning of the intervention. In addition to the possible adverse effects and 
adherence to treatment. 
The knowledge that results from this research will help to know and improve the treatment 
schemes for patients with Type 2 Diabetes Mellitus, in this case, it will allow the medical 
community to recommend the use of propolis not only to lower blood glucose but also to 
decrease the components of the disease already mentioned above. 
 
 
 
 


Possible risks and annoyances 
Discomforts or risks associated with clinical evaluation procedures: measurement of weight, 
height, blood pressure, waist, and heart rate are non-invasive clinical measurements that do 
not cause pain, discomfort, or risk. 
Discomforts or risks associated with laboratory procedures: discomfort during blood 
sampling is minimal. On some occasions, the procedure for taking a blood sample may cause 
mild pain or slight discomfort, it is possible that a bruise may form. Although there is no 
clinical evidence of adverse effects to treatment with propolis, it can cause mild intestinal 
problems if you are allergic to bees or any product made from the components of bees. In the 
case of metformin, it is also associated with gastrointestinal intolerance. 
 
Possible benefits you will receive from participating in the study 
You will not receive payment for your participation in this study, nor does it incur any 
expense to you. The treatment that you will be given is aimed at improving your blood 
glucose levels and your weight, however, it is not a guarantee of an optimal drug result. 
Although the direct benefits for you may not exist, the results of this study will contribute to 
the advancement of knowledge about the beneficial effects of this treatment in patients with 
type 2 Diabetes Mellitus, and the results will be relevant for the better management of people 
like you. Considering the above, you will be provided with the results and a clinical summary 
of what was done in the study, so that your family doctor can use it to modify and monitor 
your treatment. Your participation in this study is completely voluntary. For the purposes of 
this research, we will only use the information that you have provided us from the time you 
agreed to participate until the time you let us know that you no longer wish to participate. 
 
Privacy and confidentiality 
The information that you provide us that could be used to identify you (such as your name, 
telephone number, and address), the responses to the questionnaires, and the results of your 
clinical tests will be kept confidential to guarantee your privacy. 


The team of researchers, people involved in your health care, and your regular doctor will 
know that you are a participant in this study. However, no one else will have access to the 
information you provide to us during your participation in this study, unless you choose to 
do so. We will provide your data only if it is necessary to protect your rights or well-being 
(for example, if you suffer physical harm or need emergency care), or if required by law. 
When the results of this study are published or presented at conferences, for example, no 
information that could reveal your identity will be released. Your identity will be protected 
and hidden. To protect your identity, we will assign you a password that we will use to 
identify your data, and we will use that password instead of your name in our electronic 
databases. 
Financing 
The financing will be with own resources of the University of Guadalajara. 
 
Declaration of informed consent 
By signing this consent, I acknowledge that I have been informed about the methods and 
routes of administration of study drugs, the procedures, and tests to which I will be subjected, 
and the inconveniences, benefits, and inconveniences that may arise. I certify that I have read 
(or someone has read to me) the content of this consent form. I have had sufficient time to 
understand that all technical language used in the description of this research study has been 
satisfactorily explained to me. I received an adequate and understandable answer to all my 
questions that I have received a copy of this document, which I will keep in safe custody for 
future consultations. I’m free to withdraw from the study at any time without losing any 
benefit or suffer any penalty. I give my consent to be included in this study. 
Participant name: ___________________________________________________________ 
Participant signature: ________________________________________________________ 
Participant's address: ________________________________________________________ 
Phone: _____________________________________________ Date: _____ / _____ / ____ 


Witnesses 
Name: ___________________________________________________________________ 
Relationship: _____________________________Signature: ________________________ 
Address: __________________________________________ Date:_____ / _____ / _____ 
 
Name: ___________________________________________________________________ 
Relationship: _____________________________Signature: ________________________ 
Address: __________________________________________ Date:_____ / _____ / _____ 
 
Investigator statement 
I have explained the nature and purpose of this study to you and the possible risks and benefits 
of your participation. I have cleared all your doubts by answering all your questions. I believe 
that you understand the information described in this document and freely consent to 
participate in this research study. 
 
___________________________________  
 
 
____________________ 
Investigator's name and signature  
 
 
 
 
    Date