Clinical trial NCT03006471
Conditions: PreDiabetes Prehypertension
Keywords: Prediabetes Prehypertension Variability of blood pressure ABPM Dapagliflozin SGLT2
Sponsor: University of Guadalajara
Start date: 2016-03-30; Completion date: 2018-06-29
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Prediabetes is defined as an intermediate metabolic state that leads to the development of type 2 diabetes mellitus (DM2) and the prehypertension is a category assigned to identify patients who are at risk of developing hypertension (AH), in both pathologies the abnormalities in the variation of blood pressure (BP) has been related to organ damage, its evaluation is performed by ambulatory blood pressure monitoring (ABPM).

Dapagliflozin is a selective and reversible inhibitor of the sodium-glucose co-transporter type 2 (SGLT-2), which reduces renal reabsorption of glucose and promotes the excretion of glucose through the urine, in the way that glucose blood. Another reported effects is the decrease on BP, so it would be interesting to evaluate this effects in patients with prediabetes and prehypertension, as a potential therapy to treat disorders and to prevent progression to DM2 and Hypertension, respectively.

The aim of this study is to evaluate the effect of Dapagliflozin on variability of blood pressure in patients with prediabetes and prehypertension without pharmacological treatment.

The investigators hypothesis is that the administration of dapagliflozin decreases variability of blood pressure in patients with prediabetes and prehypertension without pharmacological treatment.

Detailed description:
A randomized, double-blind, placebo-controlled clinical trial in 30 patients with a diagnosis of prediabetes and prehypertension without treatment.

They will be assigned randomly two groups of 15 patients each to receive 10 mg of Dapagliflozin (Forxiga, Astra Zeneca) or placebo, one per day before breakfast during 12 weeks.

There will be calculated body mass index (BMI) and blood pressure variability. This protocol it's already approved by the local ethics committee and written informed consent it's going to be obtained from all volunteers.

Statistical analysis will be presented through measures of central tendency and dispersion, average and deviation standard for quantitative variables; frequencies and percentages for variable qualitative. Qualitative variables will be analyzed by X2/ exact fisher test, will be used for differences inter-group Mann-Whitney U Test and coefficient of variation, Wilcoxon Test and index of variability for the within-groups differences. It will be considered statistical significance p ≤0.05.

Arms: arm 1: Dapagliflozin capsules, 10 mg, one per day before breakfast during 12 weeks. arm 2: Placebo capsules, one per day before breakfast during 12 weeks.
Interventions: intervention 1: Dapagliflozin intervention 2: Placebo - Cap
Intervention descriptions: intervention 1: 10 mg, one per day before breakfast during 12 weeks. intervention 2: one per day before breakfast during 12 weeks.

Protocol documents:
Prot_SAP_001.pdf: 
 
 
 
 
“Effects of dapagliflozin on blood pressure variability in 
patients with prediabetes and prehypertension without 
pharmacological treatment: a randomized” 
 
 
 
 
June 9, 2016 
 
 
NCT03006471  
   


Introduction 
There is a reciprocal relationship between the possibilities of developing arterial 
hypertension (HT) and diabetes mellitus type 2 (DM2). The probability of 
developing HT in patients with DM2 is 40% in the first 5 years of diagnosis and 
12% in the development of DM2 in HT. The prevention or timely detection of these 
conditions can reduce the risk of the development of cardiovascular disease (1). 
Prediabetes and prehypertension are defined as metabolic states that lead to the 
appearance of DM2 and HT, respectively. 
Approximately 12 million people suffer from prediabetes in Mexico according to the 
report of the International Diabetes Federation (IDF) in 2017 (2). In 2015, a global 
prehypertension prevalence of 37.5% will be reported according to the 8th report 
by the Joint National Committee (JNC8) (3). 
Ambulatory blood pressure monitoring (ABPM) is superior to office BP to predict 
cardiovascular mortality and its most potent component is the alteration in 
nighttime blood pressure variability (BPV) compared to daytime (4). 
Sodium-glucose cotransporter inhibitors type 2 (iSGLT-2) are oral antidiabetics that 
improve glycemic control. Dapagliflozin promotes natriuresis and osmotic diuresis, 
which decreases plasma volume and decreases blood pressure (BP) in patients 
with DM2; however, until now it is unknown whether this effect could modify BPV in 
individuals with prediabetes and prehypertension without pharmacological 
treatment (5,6). 
 
 
 


Methods  
A clinical study, double-blind, randomized and placebo control group in 30 patients. 
Men and women (30-60 years) diagnosed with prediabetes according criteria of the 
American Diabetes Association (ADA) with fasting plasma glucose (FPG) 5.6-6.9 
mmol/L (>2 occasions) or the 2 h plasma glucose (2-h PG) value during a 75-g oral 
glucose tolerance test 7.8-11.0 mmol/L, or both (7) and prehypertension according 
criteria of the JNC8 with BP of 120-139 / 80-89 mmHg (3).  
All subjects will be sedentary, non-smokers, without HT, kidney, heart, thyroid or 
liver disease; pregnant or breastfeeding women will be excluded. They had not 
consumed any medication during the previous 6 months and all individuals had a 
stable body weight for at least 3 months prior to the study.  Withdrawal of informed 
consent, loss of follow-up, therapeutic adherence <80% and the presence of 
serious adverse effects from treatment will be considered criteria for elimination.  
Dapagliflozin (Forxiga ®Bristol-Myers Squibb, Humacao, Puerto Rico) wa given at 
a dose of 10 mg per day before breakfast for 6 months to 15 patients, while the 
remaining 15 patients received placebo in the same dose, which will be randomly 
assigned to one of the intervention groups using a table of numbers. All patients 
received general nutrition recommendations, as suggested in the ADA guidelines 
for patients with prediabetes (7), and will be instructed not to modify their usual 
physical activity.  
The enrolled subjects underwent an evaluation at 8:00 a.m. after an overnight fast 
from 10 to 12 h, will be instructed to avoid strenuous physical activity before clinical 
and laboratory tests. The body weight and height will be measure with light clothes 


and after having evacuated the bladder with digital scale Tanita® TBF-215 A 
(Corportation of American Inc.) 
The body mass index (BMI) wil be calculated as body weight (kg) divided by the 
square of the body height (m2).  
Office BP will be assessed after a period of rest with the subject sitting for 15 
minutes with a digital sphygmomanometer Omron 907-E (Healthcare, Inc.), the 
suitable cuff for the circumference of the non-dominant arm will be used (> 80% of 
the size of the circumference of the cuff) (8). The mean of three measurements of 
systolic blood pressure (SBP) and diastolic blood pressure (DBP) will be 
determined.  
The FPG and 2-h PG (mmol/l) will be quantified from the serum obtained from a 5 
ml sample of venous blood centrifuged at 2500 rpm and the amount of glucose will 
be determined by colorimetric methods with the automatic clinical chemistry 
analyzer Erba XL 100™ (Mannheim, Germany), and with an intra- and inter-assay 
coefficient of variability of < 1% and 2%, respectively. The hemoglobin glycated 
A1c fraction (A1C) (%) will be measured using high-performance liquid 
chromatography (HPLC) (Bio-Rad Laboratories, Hercules, CA, USA) with an intra- 
and inter-assay coefficient of variability of 0.4% and 1.6%, respectively.  
ABPM will be recorded during 24 h using an oscillometric method with the Microlife 
WatchBP O3 (Microlife AG, Widnau, Switzerland). BP measurement will be 
scheduled every 15 minutes during the day (8 a.m. to 11 p.m.) and every 30 
minutes during the night (11 p.m. to 8 a.m. of the next day) (8). Patients will be 
instructed to continue with the usual activities during the ABPM and they will be 
advised to remain calm when they felt the pressure increase in the cuff. The 


method will be considered reliable if more than 70% of valid measurements will be 
met.  
The BPV will be calculated: 24-h BP; daytime and nighttime BP; BP weighted 
standard deviation (SD) (the average of the daytime and nighttime BP SD each 
weighted for the duration of the respective day or night period), this method has 
been proposed as a method of excluding day to night BP changes from the 
quantification of overall 24 h SD, without discarding either daytime or nighttime 
values; the coefficient of variation (CV) of 24-h, daytime and nighttime (the average 
SD of SBP divided by the corresponding mean BP and multiplied by 100); the 
mean real variability (AVR) of SBP and DBP (the average of the absolute 
differences between consecutive BP measurements); and identify the dipper 
circadian BP pattern (BP nightly decline between 10-20% of the BP day, this is 
normal), Non-dipper (night decrease in BP <20% compared to the BP of the day), 
dipper reverse (increase in night-time BP compared to day BP), dipper extreme 
(BP nightly decline between >20% of the BP day) which are relevant to 
cardiovascular prognosis (9).  
Also, will be identified through the ABPM by 24-h: mean arterial pressure (MAP), 
daytime and nocturnal hypertensive load. 
Adherence to treatment and the presence of adverse events will be assessed with 
an attachment diary that will be given to the patient at study entry, as well as a 
record of medications and returned by patients at each visit.  
The formula for clinical trials will be used to determine the sample size (10), with a 
statistical confidence of 95% and a power of 80%, as well as the SD and the 
expected difference for each of the primary variables (11), a total of 8 and 12 


patients will be obtained for the SBP and the DBP, respectively. The highest n 
obtained will be taken into account, to which 20% will be added for possible losses. 
A total of the 15 patients per group will be estimated in this calculation. 
 
 
 
 
 


Analysis  
Data will be analyzed with the software IBM SPSS Statistics V21.0 software 
(SPSS, Inc., Chicago, IL, USA).. 
The Mann-Whitney U test (non-parametric test for quantitative variables) is used to 
evaluate the differences between the intervention groups expressed in means and 
SD; Wilcoxon (non-parametric test for quantitative variables) will be used to 
evaluate the differences between the baseline and final evaluation of each group 
expressed in means and SD; and Pearson's Chi2 or Fisher's exact test (non-
parametric test for qualitative variables) will be used to evaluate the differences 
between the intervention groups expressed in frequencies and percentages. 
A p≤0.05 is considered statistically significant.  
The present study will be consistent with the Helsinki declaration and will be 
approved by the Local Committee of Ethics and Research of the University with 
this register number CEI/357/2016 and Clinical Trials NCT03006471. The informed 
consent will be obtained from the participants before performing any intervention or 
evaluation. The principal investigator explained to each participant the nature, risks 
and benefits of the study. 
 
 
 
 
 
 
 
 


Financing  
The financing will be with own resources by the University of Guadalajara. 
 
 


References 
1. 
International Diabetes Federation. Atlas de la diabetes de la FID. 2015 
[updated in 2015]. Available from: 
https://www.fundaciondiabetes.org/upload/publicaciones_ficheros/95/IDF_Atlas_20
15_SP_WEB_oct2016.pdf. 
2. 
Rodríguez-Ramirez M, Simental-Mundía LE, González-Ortiz M, Martínez-
Abundis E, Madero A, Brito-Zurita O, et al. Prevalence of Prehypertension in 
Mexico and Its Association With Hipomagnesemia. Am J Hypertension 2015; 28: 
1024-1030.  
3. 
Parati G, Ochoa JE, Lombardi C, Bilo G. Assessment and management of 
blood-pressure variability. Nat Rev Cardiol 2013; 10: 143-155.  
4. 
Rothwell PM. Limitations of the usual blood-pressure hypothesis and 
importance of variability, instability, and episodic hypertension. Lancet 2010; 375: 
938-948.  
5. 
Sternlicht H, Bakris GL. Blood pressure lowering and sodium-glucose co-
transporter 2 inhibitors (SGLT2is): more than osmotic diuresis. Curr Hypertens Rep 
2019; 21: 12. 
6. 
Wilding JP. The role of the kidneys in glucose homeostasis in type 2 
diabetes: Clinical implications and therapeutic significance through sodium glucose 
co-transporter 2 inhibitors. Metabolism 2014; 63: 1228-1237.   
7. 
Oliva RV, Bakris GL. Blood pressure effects of sodium–glucose cotransport 
2 (SGLT2) inhibitors. J Am Soc Hypertens 2014; 5: 330-339. 
8. 
Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Avivit C, et al. 
Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2018; 


380: 347-357.  
9. 
American Diabetes Association: Classification and Diagnosis of Diabetes: 
Standards of Medical Care in Diabetes—2019. Diabetes Care 2019; 42 (Suppl 1): 
S13-28. 
10. 
James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, 
Handler J, et al. 2014 evidence-based guideline for the management of high blood 
pressure in adults: Report from the panel members appointed to the Eighth Joint 
National Committee (JNC 8) JAMA. 2014; 311: 507-520. 
11. 
Whelton PK, Carey RM, Aronow WS, Casey DE, Collins KJ, Dennison-
Himmerlfarb C, et al. Guideline for the prevention , detection, evaluation and 
management of high blood pressure in adults: a report of the American College of 
Cardiology / American Heart Association Task Force on Clinical Practice 
Guidelines. J Am Coll Cardiol 2018; 71: e127-e248. 

ICF_000.pdf: 
 
1
 
 
 
 
 
“Effects of dapagliflozin on blood pressure variability in 
patients with prediabetes and prehypertension without 
pharmacological treatment: a randomized” 
 
 
 
 
June 9, 2016 
 
 
NCT03006471  
   


 
2
INFORMED CONSENT FORM 
 
“Effects of dapagliflozin on blood pressure variability in patients with 
prediabetes and prehypertension without pharmacological treatment: a 
randomized” 
 
 
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 
Prediabetes and prehypertension are conditions that have a high risk of 
developing type 2 diabetes mellitus and hypertension respectively and are 
considered a major health problem in the world. Early detection and control of 
high blood pressure and high blood glucose levels prevent heart disease to a 
large extent. 
The purpose of this study is to evaluate your general health conditions, 
detect, monitor, control or lower glucose levels and blood pressure. Our study is 
focused on measuring your blood glucose as well as your blood pressure with an 
instrument called ambulatory blood pressure monitoring, also called ABPM 
during a period of 24 hours with the administration of dapagliflozin or placebo in 
patients with prediabetes and prehypertension without drug treatment. 
 
Study description 
30 patients participated in this study; 2 groups (15 patients per group) randomized 
to one of the following treatments: 
■ Dapagliflozin: it is a drug used to treat patients with type 2 diabetes 
mellitus, it acts at the renal level; causes the elimination of glucose, water 
and salt in the urine, in this way the levels of glucose in the blood decrease 
as well as the blood pressure. 
■ Placebo: it is the same shape, size and color as dapagliphozin, it looks like 
a medicine but it is not; therefore, it will not have any effect on your body, 
much less on your blood pressure. 
During this study; your doctor in charge, nor you, will know which group you 
belong to, nor will they know who takes dapagliflozin or placebo (only a person 
outside the research will know), or on the contrary that some circumstance 
requires it. 
Both medications will be provided free of charge, with a sufficient quantity and 
with instructions on how to take it. 


 
3
 
The study will be 3 months, with 8 visits: 
■ Visita 1 (Día -7 a -2): 
All possible candidates will be summoned at 08:00 am with a 12 hour fast. In 
this first visit, information regarding the study is provided; the objectives, 
characteristics, procedures, as well as its potential benefits and risks. If the 
individual accepts and the investigator in charge decides that the patient meets 
the clinical criteria for participation in the study, the informed consent will be 
signed. 
A medical history will be taken, anthropometric measurements and vital signs 
(weight, height, BMI and office BP) will be taken. A blood sample (5 ml of blood) 
will be taken to measure fasting plasma glucose and hemoglobin glycated A1c 
fraction. 
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 approximate time is 30 minutes. 
 
■ Visit 2 (Day -1): 
Laboratory results are assessed and it is confirmed that the individual meets 
all the clinical and laboratory inclusion criteria, if so, ABPM will be placed for 24 
hours at 8 am ± 2-h- 
 
■ Visit 3 (Day 0) 
24 hours after the placement of the ABPM, the patient is scheduled for 
removal. Their treatment is randomized by another investigator outside the 
present study, either in the dapagliflozin group or in the placebo group. 
A diary will be given to the patient where the daily dosage is described, in 
addition the medication corresponding to the first month of the intervention will be 
delivered and finally general nutrition recommendations will be given since during 
the study it is not indicated to start some type of diet to lose weight. Weight or an 
increase in physical activity. The control patient will be given an appointment 30 
and 60 days respectively after starting treatment. 
 
■ Visit 4 and 5 (Days 30.60 ± 2 respectively) 
During the first and second months of the intervention, you will be summoned 
to monitor adherence and tolerability to the treatment through the diary, clinical 
measurements and capillary blood glucose, vital signs will be taken and the 
medication corresponding to the current month will be provided. 
 
■ Visit 6 (Day 90 ± 2) 
After 90 days at the beginning of the intervention, the individual will be 
summoned again and the clinical and laboratory measurements will be taken in 
the same way as they will be done in the baseline visit, with a 12-hour fast, the 
ABPM will be placed for 24 hrs. 


 
4
 
■ Visit 7 (Day 91 ± 2) 
24 hrs after placement of the ABPM, the patient is scheduled for removal at 8 
am ± 2-h. 
 
■ Visit 8 (Day 120 ± 2) 
Within the first 4 weeks, the patient will be summoned to deliver the final 
results and their evolution during the intervention will be explained. Finally, you 
will be given medical-nutritional recommendations to continue treatment if the 
patient requires it. 
 
The present study was consistent with the Helsinki declaration and was 
approved by the Local Committee of Ethics and Research of the University with 
this register number CEI/357/2016. This informed consent will be obtained from 
the participants before performing any intervention or evaluation. The principal 
investigator explained to each participant the nature, risks and benefits of the 
study. 
New information  
During the course of this study, we will inform you of any findings and in the 
event of new interventions we will again request your written consent. 
 
Risks of the intervention 
During the collection of blood samples, one or more punctures (taking 
blood with a needle and syringe) will be required in any of the veins in your arms, 
during which you may feel pain and occasionally a bruise may form. In the area 
where the blood is taken. 
In order to avoid unnecessary risks for you and your family, the medicine that is 
given or strictly prescribed should be consumed only by you and in the way that 
is indicated. 
You could have: back pain, dizziness, increased urinary frequency, pain when 
urinating, genital and urinary tract infections, changes in kidney function 
(creatinine), these discomforts occur rarely, as it will depend on each patient. It 
is essential that you inform the treating doctor in this investigation of all the 
discomfort you may suffer throughout the study since your treating doctor knows 
the best way to treat them, which may include stopping treatment. 
 
Benefits of the intervention 
You will not receive payment for your participation in this study, nor does 
this study imply any expense for you, instead you will benefit from a medical 
evaluation, clinical and laboratory measurements. At the end of the study, you 
will be given professional and multidisciplinary medical and nutrition guidance if 
necessary. 
Hospital visits, procedures and medication will be at no cost to you if 
necessary during our intervention. 


 
5
Although the direct benefits for you may not exist, the results of this study 
will contribute to the advancement of scientific knowledge for new applications 
with the use of dapagliflozin, as well as for the management of people who, like 
you, have the same problem. 
 
Participation or withdrawal from the study 
Your participation in our study is completely voluntary. You can decide not 
to enter or discontinue your participation, with a prior visit with your treating 
doctor, as well as he may suspend your participation without your consent if you 
need additional treatment, do not follow the instructions or there is suspicion that 
the medicine is harmful to your health. However, you will still have the benefit of 
medical care and follow-up. 
 
 
Privacy and confidentiality 
The information provided to us will be confidential to guarantee your 
privacy, including the presentation of the results at congresses or conferences, 
unless your health is at risk and / or you so wish. 
 
Financing  
The financing will be with own resources by the University of Guadalajara. 
 
 
Declaration of informed consent 
What this study consists of has been clearly explained to us; the methods, 
procedures, administration of the drug, as well as the benefits and adverse effects 
that may occur. I have also read and / or someone has read to me the content of 
this consent. We have been given the opportunity to ask questions and they have 
been answered in plain language and there has been no doubt, and I have been 
provided with a copy of this form. 
I understand that we are free to withdraw from the study at any time with 
prior notice to the researchers of our reasons, without losing benefits or obtaining 
any penalty. We freely and without reservation give our consent to participate as 
a patient in this study. 
 
 
 
Date: _____ / _____ / _____ 
Participant name: _________________________________________________ 
Participant Signature: ______________________________________________ 
Participant´s address: ______________________________________________ 
Phones:_________________________________________________________ 
 
 
Witness 1 
 
 
 
 
 
       Date: _____ / _____ / _____ 
Name: ____________________________Relationship to patient:___________  


 
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Signature: _______________________________________________________ 
Address: ________________________________________________________ 
 
Witness 1 
 
 
 
 
 
       Date: _____ / _____ / _____ 
Name: ____________________________Relationship to patient:___________  
Signature: _______________________________________________________ 
Address: ________________________________________________________ 
 
Investigator Statement   
 
 
      Date: _____ / _____ / _____ 
 
Manager's name and signature:______________________________________