Impact on Glycemic Variability in Newly Onset T2DM Patients Initiating Dapagliflozin Plus Metformin Versus Metformin Alone: A Randomized Open Label Clinical Study. The MAGNNIFY Trial.
Phase: PHASE3
Conditions: Type 2 Diabetes
Sponsor: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

 
 
 
 
 
 
 
EFFECTS OF EARLY USE OF DUAL THERAPY OF DAPAGLIFLOZIN 
WITH METFORMIN ON GLYCEMIC VARIABILITY IN MEXICAN 
PATIENTS WITH TYPE 2 DIABETES MELLITUS.  
AN OPEN-LABEL RANDOMIZED CLINICAL TRIAL. 
4th Version, May 6, 2021 
 
NCT NUMBER NCT04090580 
 
 
 
 

Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán 
Research Ethics Committee/Research Committee 
Application for evaluation of research protocols 
 
Project Title 
EFFECTS OF EARLY USE OF DUAL THERAPY OF DAPAGLIFLOZIN WITH METFORMIN ON 
GLYCEMIC VARIABILITY IN MEXICAN PATIENTS WITH TYPE 2 DIABETES MELLITUS.  
AN OPEN-LABEL RANDOMIZED CLINICAL TRIAL. 
4th Version, May 6, 2021 
Type of Research 
Type of research Select an option 
Pharmacological 
x 
Biomedical 
 
Epidemiological 
 
Interchangeability 
 
Other 
 
Investigators 
Investigator 
Institutional Position 
Project 
Position 
Phone 
ext. 
Miguel Ángel Gómez 
Sámano 
Specialist Physician A 
Principal 
Investigator 
2405 
Valerie Paola Vargas 
Abonce 
UNAM Master's in Medical Sciences 
Student 
Associate 
Investigator 
2405 
Anna 
Paula 
Guerrero Castillo 
Medical Intern Social Service 
Associate 
Investigator 
2405 

Francisco J Gómez 
Pérez 
Head of Endocrinology 
Associate 
Investigator 
2405 
Daniel 
Cuevas 
Ramos 
Specialist Physician A 
Associate 
Investigator 
2405 
Gerardo 
Gamba 
Ayala 
Director of Research 
Associate 
Investigator 
6109 
Alberto 
Sigfrido 
Benítez Rentería 
Surgeon (Belongs to AstraZeneca Medical 
Dept.) Conflict of interest declared 
Associate 
Investigator 
2405 
Alejandra 
Silva 
Giordano 
Endocrinologist (Belongs to AstraZeneca 
Medical Dept.) Conflict of interest declared 
Associate 
Investigator 
2405 
Lucía Palacios Báez 
Research Studies Coordinator 
Associate 
Investigator 
2405 
María 
Guadalupe 
López Carrasco 
ICM-A 
Associate 
Investigator 
2437 
Sandra 
Rodríguez 
Carranza 
Specialist Physician A 
Associate 
Investigator 
2405 
Jessica 
Bahena 
López 
Research Physician 
Associate 
Investigator 
2405 
Lorena Rojas Vega 
Research Physician 
Associate 
Investigator 
2405 
Griselda Xóchitl Brito 
Córdoba 
Nutritionist 
Associate 
Investigator 
2405 
Iliana Manjarrez 
Nutritionist 
Associate 
Investigator 
2405 
 

Relevance of the research group to the project 
Investigator 
Research study experience 
Miguel Ángel Gómez Sámano 
Extensive 
Valerie Paola Vargas Abonce 
In training 
Anna Paula Guerrero Castillo 
In training 
Francisco J Gómez Pérez 
Extensive 
Gerardo Gamba Ayala 
Extensive 
Daniel Cuevas Ramos 
Extensive 
Sigfrido Benítez Rentería 
Extensive 
Alejandra Silva Giordano 
Extensive 
Lucía Palacios Báez 
Extensive 
María Guadalupe López Carrasco Extensive 
Sandra Rodríguez Carranza 
Extensive 
Jessica Bahena López 
Extensive 
Lorena Rojas Vega 
Extensive 
Griselda Xóchitl Brito Córdoba 
Extensive 
Iliana Manjarrez 
Extensive 
 
 
 

Participating Institutions 
Institution 
(Company 
name 
and address) 
Role in the 
project 
Granted project 
approval? 
"Instituto Nacional de Ciencias de 
Médicas 
y 
Nutrición, 
Salvador 
Zubirán" 
 
Site 
Yes 
Sponsorship 
Sponsoring organizations 
The study was designed by the principal investigator, without interference from the 
pharmaceutical industry. 
The project will receive financial support from AstraZeneca, which will provide the research 
product and financial support for its execution (supplies, laboratory costs, and associated 
publication costs). 
Specify if investigators receive payment (monetary or in-kind) for their specific participation 
in the research. 
No payment of any kind is received. 
 
Summary (Limit 400 words) 
Type 2 Diabetes is one of the most prevalent chronic diseases and constitutes the eighth leading 
cause of death and disability due to its micro and macrovascular complications. 
Chronic hyperglycemia induces a proinflammatory cascade and the formation of free radicals, 
such as superoxide and hydrogen peroxide, which generate a state of oxidative and mitochondrial 
stress, causing irreversible damage to cell membranes and interfering with various cellular 
signaling pathways, being the main pathophysiological mechanism for the development of 
microvascular complications. 
Therefore, the treatment of Diabetes focuses on reducing exposure to hyperglycemia, and 
intensive glycemic control has been shown to decrease the risk of microvascular complications, 
especially if implemented from diagnosis. 
However, most pivotal studies on intensive glycemic control were developed before modern 
medications such as SGLT2 inhibitors and GLP-1 agonists. 
 

Glycated hemoglobin (HbA1c) is the standardized marker to assess glycemic control, since it 
reflects the average glycemia of the last 3 months. However, it does not detect short-term glucose 
fluctuations or hypoglycemic episodes.  
Glycemic variability (GV), which refers to daily glucose fluctuations, including preprandial, 
postprandial glycemia, and hypoglycemic episodes, could be associated with an increase in 
oxidative stress and the development of microvascular complications in Type 2 Diabetes (T2D). 
Although SGLT2 inhibitors have been shown to reduce GV, there is no evidence regarding their 
effect in newly diagnosed T2D patients when used at the initiation of pharmacological therapy, 
nor regarding their impact on oxidative stress. 
Main objective: To evaluate the effect of dual therapy with Dapagliflozin + Metformin (DAPA/MET) 
versus Metformin monotherapy (MET) over 12 weeks on GV in patients with T2D. 
Secondary objectives: To evaluate the effects on HbA1c, insulin, plasma antioxidant capacity, 
body composition, and cardiometabolic risk factors. 
Hypothesis: The reduction in glycemic variability (measured using the mean amplitude of glycemic 
excursions, MAGE) will be greater in patients receiving dual therapy with Dapagliflozin + 
Metformin compared to those receiving Metformin monotherapy. 
Methods: 88 patients with T2D without catabolic symptoms or complications, with HbA1c >7.5% 
and <12% and BMI >25 kg/m2 will be included. Patients will be randomized 1:1 to receive 
Dapagliflozin 10 mg/day + Metformin 2000 mg/day (n=44) or Metformin 2000 mg/day (n=44). GV 
will be measured with the iPro™ CGM system (Medtronic) at baseline and the end of the 12 
weeks of treatment. 
Statistical analysis: The primary dependent variable will be MAGE as a marker of GV. Other 
variables such as HbA1c, serum insulin, plasma antioxidant capacity, VCAM-1, and adiponectin 
will be analyzed. Change deltas will be calculated for each group and compared using ANCOVA. 
A p-value ≤0.05 will be considered significant. All analyses will be performed with SPSS 20.0. 
 
Background 
There is growing evidence regarding the beneficial effects of sustained intensive glycemic control 
on the incidence and progression of complications in T1D and T2D [1]. HbA1c has been the main 
marker used to define glycemic control because it provides an average of glycemia in the 2 or 3 
months before its measurement, with the American Diabetes Association recommending that 
HbA1c levels be maintained between 6.5% and <8%, depending on the individual characteristics 
of each patient [2]. Although HbA1c is a standardized, validated, and evidence-based marker, it 
is not useful for evaluating glycemic fluctuations over short periods [1]. 

Glycemic variability (GV) is defined as fluctuations in blood glucose throughout the day, including 
preprandial, postprandial glycemia, and hypoglycemic episodes [2]. It is important to evaluate the 
effect of oral hypoglycemic treatments on GV because evidence suggests it could be significantly 
involved in the generation of oxidative stress and consequent endothelial dysfunction [3], and thus 
has been proposed as a determinant in the development of microvascular complications of T2D 
[6-8]. 
In a cross-sectional study of 26 patients with T1D, GV was found to be associated with endothelial 
and cardiovascular damage, even when the average HbA1c was reported as 6.7% [4]. In a 
retrospective cohort of 748 patients with T2D and heart failure, the GV index showed an 
independent association with mortality, also independent of the presence of hypoglycemic events 
[5]. In a sub-analysis of the ADVANCE study involving 4399 T2D patients, visit-to-visit GV in 
HbA1c was independently associated with the risk of vascular events (p=0.01) and mortality 
(p<0.001). Furthermore, variability in HbA1c was positively associated with the risk of 
macrovascular events, and variability in fasting glucose was associated with micro and 
macrovascular complications [6]. In another study of 68 T2D patients followed for 4.8 years, visit-
to-visit HbA1c variability was associated with cognitive decline [7]. GV estimated by MAGE was 
the most important risk factor associated with diabetic peripheral neuropathy in T2D patients with 
controlled glycemia (HbA1c <7.0%) [8]. In another study of 110 T2D patients, the coefficient of 
variation and HbA1c variability were independently associated with the presence of cardiac 
autonomic neuropathy [9]. In a sub-analysis of the DEVOTE study, increased day-to-day GV was 
associated with a higher presence of major cardiovascular events (HR 1.36, 95% CI 1.12, 1.65) 
and higher all-cause mortality (HR 1.58, 95% CI 1.23, 2.03) [10]. Finally, a systematic review and 
meta-analysis found that HbA1c variability was associated with kidney disease (RR 1.56), 
cardiovascular events (RR 1.98), and retinopathy (RR 2.11) in T1D patients, and with kidney 
disease (RR 1.34), macrovascular events (RR 1.21), presence of ulcers and gangrene (RR 1.5), 
cardiovascular disease (RR 1.27), and mortality (RR 1.34) in T2D patients [11]. 
It is known that "total glycemic exposure" (mean HbA1c values and duration of diabetes) accounts 
for 11% to 23% of microvascular complications [17,18]. This implies that more than 75% of these 
complications are based on etiopathogenic and pathophysiological mechanisms different from 
sustained hyperglycemia. Exposure to glycemic disorders can be described based on 2 
components: the duration and magnitude of chronic sustained hyperglycemia (HbA1c), which 
depends on interprandial and postprandial hyperglycemia, modulating the percentage of each 
contributor by the degree of control [19], and acute glucose fluctuations during a daily period [20-
24]. 

Hyperglycemic states trigger harmful metabolic events through a single process: the 
overproduction of superoxide by the mitochondrial electron transport chain. This theory seems to 
indicate that the activation of oxidative stress by hyperglycemia plays an important role in the 
pathogenesis of diabetic complications. Because all these metabolic alterations occur more 
particularly in endothelial cells, it has been postulated that they can cause endothelial dysfunction 
and contribute to vascular damage [25-26]. The results of Monnier et al. [5] in patients with T2D 
suggest a very significant relationship between GV, determined by continuous glucose monitoring 
and calculated using MAGE, and the urinary excretion of 15(S)-8-iso-PGF2α, a marker of 
oxidative stress. In patients with T1D, Ceriello et al. [27] report that acute hyperglycemia seems 
to worsen endothelial function and increase the inflammatory response and oxidative stress, 
regardless of the duration of the disease and previous glycemic control. 
Some epidemiological studies have reported that obesity, atherosclerosis, insulin resistance, and 
diabetes mellitus are associated with a chronic inflammatory state, less intense than the acute 
phase reaction secondary to the secretion of different adipocytokines (IL-6, TNF-α, leptin, 
adiponectin), which influence the regulation of the atherogenic process and insulin resistance 
[28]. Low plasma levels of adiponectin have been detected in diabetes mellitus [29], and Stefan 
et al. [30] have found a negative correlation between plasma adiponectin and endogenous 
glucose production, supporting a role for this hormone in glucose metabolism. Different studies 
have shown that adiponectin has anti-atherogenic and anti-inflammatory properties, including 
suppression of macrophage phagocytosis and inhibition of foam cell formation, reduction of TNF-
α secretion, migration of smooth muscle cells to the arterial wall, and blockade of excessive 
platelet adhesion [31]. 
There is no conclusive information in the literature regarding the possible contribution of GV to 
the development of chronic complications in diabetic patients. However, in vitro experiments, 
animal models, and some clinical trials conducted in humans show that acute fluctuations in 
glucose concentrations increase oxidative stress, inflammatory response, and endothelial 
damage [5, 27, 32]. Currently, GV measures such as having a coefficient of variation < 36% are 
recommended as treatment goals for T2D [12], and the use of drugs such as exenatide [13], 
acarbose [14], saxagliptin [15], dapagliflozin [16], liraglutide [17], and dulaglutide [18] has been 
shown to improve GV. 
Sodium-glucose cotransporter 2 inhibitors [19] (SGLT2i) are a new therapeutic option for glycemic 
control in T2D patients. As their name suggests, they act by inhibiting the sodium-glucose 
cotransporters responsible for renal glucose reabsorption in the proximal convoluted tubule 
(SGLT1 and SGLT2). Various formulations of these inhibitors have been developed, among which 

Canagliflozin, Dapagliflozin, and Empagliflozin are the most studied and approved. Their clinical 
use results in the urinary excretion of 70 to 90 g of glucose [20], mostly reducing HbA1c by 0.6 to 
1% [59]. They modestly reduce blood pressure and affect weight loss. The risk of hypoglycemia 
is low because their effect decreases when the filtered glucose level is lower than the reabsorption 
capacity of SGLT1 [21]. Their main associated complications are an increased risk of fungal and 
bacterial genitourinary infection, dizziness, and postural hypotension. The ADA recommends their 
use in combination therapy with Metformin as a second line in patients not meeting targets with 
monotherapy and those who have a high risk of cardiovascular disease, chronic kidney disease, 
and/or heart failure [22]. 
Dapagliflozin is a highly selective, reversible inhibitor of the sodium-glucose cotransporter type 2 
(SGLT2i) that improves glycemic control independently of insulin secretion or action by reducing 
the reabsorption of filtered glucose and increasing urinary glucose excretion. By inhibiting SGLT2 
with dapagliflozin, the renal threshold for glucose reabsorption (90%) is reduced, causing 
increased glucose excretion in the urine, thereby lowering fasting and postprandial 
hyperglycemia. The use of dapagliflozin is associated with a reduction in body weight, secondary 
to increased glucose elimination and related caloric loss, and also with a reduction in blood 
pressure, apparently related, at least in part, to its mild diuretic effect and the associated reduction 
in body weight. 
The guidelines of the American Association of Clinical Endocrinologists recommend the use of 
combination therapy with MET + another glucose lowering medication when HbA1c at diagnosis 
is >7.5 and ≤ 9%, and in patients with HbA1c >9% without classic symptoms of diabetes; dual or 
triple therapy can also be initiated [23]. In a study of 16 T2D patients, dapagliflozin 5 mg showed 
statistically significant improvement in body composition (fat mass) from week 8 [49]. In another 
study of 40 hypertensive patients treated with dapagliflozin vs hydrochlorothiazide, an impact on 
blood vessel vasodilation was found after 4 weeks of dapagliflozin treatment [50]. The effect of 
administration of dapagliflozin decreased glycemic excursions, reduced GV, and prevented 
atherosclerosis damage in preclinical studies [45]. In a case report of a patient with MODY, 
administration of gliclazide with dapagliflozin improved GV [46]. 
Henry et al. [37], using CGM, determined GV in patients with uncontrolled T2D (HbA1c 7.5% to 
10.5%) who were previously treated with Metformin >1500 mg/day (50%) or insulin > 30 units/day 
(50%), to whom dapagliflozin or placebo was additionally administered. A decrease of 18.2 mg/dL 
in average glucose with CGM and a decrease of 15.3 mg/dL in MAGE were reported. Based on 
this study, the sample size calculation was performed. 
9. Problem Definition 

HbA1c reflects the mean glucose concentration over the last 8 to 12 weeks. It is well documented 
that elevated HbA1c levels are associated with an increased risk of diabetes complications. 
However, evidence has shown that glycemic variability, particularly MAGE, is associated with 
greater vascular endothelial dysfunction and oxidative stress, consequently increasing the risk of 
developing retinopathy, nephropathy, and coronary artery disease. A frequently used measure of 
GV is MAGE, which reflects the mean of the differences between consecutive peaks and nadirs 
of blood glucose concentrations and is therefore independent of the mean glucose level [47]. 
Correcting GV is currently considered a clinical objective to reduce average glycemia and 
determine its direct effects on vascular complications in diabetes. Sodium-glucose cotransporter 
type 2 inhibitors have been shown to be effective in improving glycemic control, in terms of fasting 
glycemia, glycated hemoglobin, and glycemic variability determined by MAGE. However, the 
evidence primarily considers their use in Type 2 Diabetes patients diagnosed more than 5 years 
prior and previously treated with other pharmacological regimens, including insulin. Therefore, the 
effect of SGLT2i on glycemic variability and oxidative stress when used in patients with a recent 
diagnosis of Type 2 Diabetes is unknown. 
10. Justification 
Type 2 Diabetes is one of the most prevalent chronic diseases worldwide and constitutes the 
eighth leading cause of death and disability due to its micro and macrovascular complications. 
Chronic hyperglycemia, through the production of advanced glycation end products, induces a 
proinflammatory cascade involving mainly Interleukin 6, Tumor Necrosis Factor-alpha, and the 
formation of free radicals, such as superoxide and hydrogen peroxide. This generates a state of 
oxidative and mitochondrial stress, causing irreversible damage to cell membranes and interfering 
with various cellular signaling pathways, representing the main pathophysiological mechanism for 
the development of microvascular complications. For this reason, the current treatment of 
Diabetes focuses primarily on reducing exposure to hyperglycemia, and intensive glycemic 
control has been shown to decrease the risk of microvascular complications, especially if 
implemented early after diagnosis. 
However, most pivotal studies on intensive glycemic control predate the existence of medications 
such as SGLT2 inhibitors and GLP-1 agonists. Glycated hemoglobin (HbA1c) is the most widely 
used standardized marker for evaluating glycemic control, as it reflects the average glycemia over 
the last 3 months. However, it does not detect short-term glucose fluctuations or hypoglycemic 
episodes. Glycemic variability (GV), which refers to daily glucose fluctuations including 
preprandial, postprandial glycemia, and hypoglycemic episodes, could be associated with 
increased oxidative stress and the development of microvascular complications in Type 2 

Diabetes (T2D). There is increasing information about the reduction in the risk of microvascular 
complications when decreasing glycemic variability is considered a treatment goal in both Type 1 
and Type 2 Diabetes. SGLT2 inhibitors have demonstrated reduced GV and their beneficial 
cardiovascular and renal effects are now well known. Although the American Diabetes 
Association recommends their use in concomitant therapy with Metformin as a second line in 
patients not meeting targets with monotherapy and those with high risk of cardiovascular disease, 
chronic kidney disease, and/or heart failure, clinical endocrinologists are increasingly inclined to 
initiate T2D treatment with dual therapy including Metformin and an SGLT2i or a GLP-1 agonist 
when HbA1c at diagnosis is >7.5% and ≤ 9%, and in patients with HbA1c >9% without classic 
diabetes symptoms. Understanding the effect of SGLT2i on glycemic variability and markers of 
oxidative stress when used early in the diagnosis of Diabetes would allow establishing a line of 
research on their effect in reducing the risk of microvascular complications, thereby having a 
positive impact on the global burden of the disease. 
Hypothesis 
The reduction in glycemic variability (measured using the mean amplitude of glycemic excursions, 
MAGE) will be greater in patients receiving dual therapy with Dapagliflozin + Metformin compared 
to patients receiving Metformin monotherapy. 
Objectives 
Main Objective 
To evaluate the effect of dual therapy of Dapagliflozin + Metformin (DAPA/MET) versus Metformin 
monotherapy (MET) on GV in patients with T2D after 12 weeks of treatment. 
Specific Objectives 
• 
To compare the effect of dual therapy of Dapagliflozin + Metformin versus Metformin 
monotherapy on HbA1c levels (%). 
• 
To compare the effect of dual therapy versus monotherapy on plasma antioxidant capacity. 
• 
To compare the effect of dual therapy versus monotherapy on inflammation biomarkers 
(VCAM-1 and adiponectin). 
• 
To compare the effect of dual therapy of Dapagliflozin + Metformin versus Metformin 
monotherapy on cardio-metabolic risk factors (weight (kg), BMI (kg/m2), total cholesterol 
(mg/dL), HDL (mg/dL), LDLc (mg/dL), albuminuria (mg/24 hr), and blood pressure (mmHg)) 
in patients with T2D, after 12 weeks of treatment. 
 
 

Methods 
GENERAL DESIGN 
STUDY DESIGN. Randomized, open-label, prospective, longitudinal phase IV clinical trial. 
POPULATION. Adult men and women aged 18 to 77 years who meet the following Inclusion 
Criteria: Diagnosis of Type 2 Diabetes, with HbA1c 7.5% <12%, with BMI ≥ 25 kg/m2. 
Exclusion Criteria: HbA1c >12%, T2D-related complications, HbA1c >9% with catabolic 
symptoms, creatinine clearance by CKD-EPI <60 ml/min/1.73m2, Type 1 Diabetes or LADA, 
Concomitant clinically significant disease such as: liver, hematological, oncological, psychiatric or 
rheumatic disease, symptoms of severe glycemic dyscontrol such as marked polyuria or 
polydipsia + 10% weight loss within the last 3 months before enrollment, Known hypersensitivity 
to dapagliflozin or metformin or any of the drug excipients, Patients with bariatric surgery, Any 
major CV event / vascular disease within 3 months before signing consent at enrollment, 
pregnancy or lactation period, being hospitalized or having less than one month since hospital 
discharge for any cause. 
SAMPLE SIZE. Using the difference of means formula and based on Henry et al., a reduction in 
glucose variability from 4.85 to 2.2 was estimated with an expected standard deviation of 2.8 in 
the MAGE index, with a statistical power of 80% and a confidence level of 95%. A total of 88 
participants were obtained, 44 individuals in each treatment group. The CDC Epi InfoTM software 
was used. Patients will be randomized 1:1 to receive Dapagliflozin 10 mg/day + Metformin 2000 
mg/day (n=44) or Metformin 2000 mg/day (n=44). GV will be measured with the iPro™ CGM 
system (Medtronic) at baseline and at the end of the 12 weeks of treatment. 
VARIABLES. The primary dependent variable will be MAGE as a marker of GV. Other variables 
such as HbA1c, serum insulin, plasma antioxidant capacity, VCAM-1, and adiponectin will be 
analyzed. The independent variable will be the treatment group. 
STATISTICAL ANALYSIS. Quantitative variables with normal distribution according to the 
Kolmogorov-Smirnov test will be expressed as Means ± Standard Deviation. Quantitative 
variables with non-normal distribution will be expressed as Medians (Interquartile Range 25-75). 
Categorical variables will be expressed as proportions (percentages). Change deltas will be 
calculated for each group and compared using ANCOVA, considering age, sex, BMI, baseline 
HbA1c, and time since Diabetes diagnosis as covariates. A p-value ≤0.05 will be considered 
significant. All analyses will be performed with SPSS 22.0. 
 
 
 

Study Timeline 
Study Type 
Select an option 
Retrospective  
Prospective 
X 
Process of assigning study groups 
Maneuver 
Yes (Include corresponding information) No Not applicable 
Randomization 
X 
 
 
Open-label study 
X 
 
 
Single-blind study 
 
X 
 
Double-blind study  
X 
 
Triple-blind study 
 
X 
 
Description of maneuvers or interventions 
● Clinical History: Will be conducted via telemedicine (Phone call/Videocall, Whatsapp, 
Teams, Zoom, Google Forms) at visit 1 DP of the treatment period. 
● Diet Plan Prescription: Will be conducted via telemedicine (Phone call/Videocall, 
Whatsapp, Teams, Zoom, Google Forms) at visit 2 DP of the treatment period. 
● Anthropometric Measurements and Physical Exam: Will be performed at visits 1 DP, 3 
DP, 4 DP, and 6 DP of the treatment period. 
● GV Monitoring: Both groups will be monitored before treatment and at the end. The iPro ™ 
CGM system (Medtronic, Northridge, CA) will be used. Baseline continuous glucose 
monitoring will begin in week 1 (Visit 1DP) and end seven days later at Visit 2DP (day 1, 
Week 2). End-of-treatment continuous glucose monitoring will begin at Visit 5 DP (week 12) 
and end 7 days later (Visit 6 DP). 
● Measurement of HbA1c and Insulin Levels: Will be performed at visits 1DP and 6DP of 

the treatment period. 
● Spot Urine Sample: Will be collected at Visits 1DP, 3DP, 4DP, and 6DP. 
● Measurement of Oxidative Stress and Inflammation Biomarkers: Will be performed at 
visits 1DP, 3DP, 4DP, and 6DP of the treatment period. 
● WHO Physical Activity Questionnaire: Will be evaluated via telemedicine (Phone call, 
Whatsapp, Teams, Zoom, Google Forms) at visits 1DP, 3DP, 4DP, and 6DP of the treatment 
period. 
● Food Record: Will be performed at visits 1 FP, 2 FP, 1 DP, 2 DP, 3 DP, 4 DP, 5 DP, and 6 
DP of the treatment period. The patient will keep a daily record, and data will be collected via 
Phone call/Videocall, or e-mail.  
Table of Times and Events 
Procedure 
Visit 
1 FP 
Visit 2 
FP 
Visit 1 
DP 
Visit 2 
DP 
Visit 3 
DP 
Visit 4 
DP 
Visit 5 
DP 
Visit 6 
DP 
 
Week 
-2 
Week -
1 
Week 0 Week 1 Week 5 Week 9 Week 
12 
Week 
13 
Informed 
Consent 
 
 
x 
 
 
 
 
 
Weight 
and 
Height 
 
 
x 
 
x 
x 
 
x 
Pre-
randomization 
Inclusion 
Criteria* 
x 
 
 
 
 
 
 
 
Clinical History 
 
 
x 
 
 
 
 
 
MET Tolerance 
Evaluation 
 
x 
 
 
 
 
 
 
Inclusion 
and x 
 
 
 
 
 
 
 

Exclusion 
Criteria 
Anthropometric 
Measurements 
(weight, waist 
circ., 
blood 
pressure) 
 
 
x 
 
x 
x 
 
x 
Physical Exam 
 
 
x 
 
x 
x 
 
x 
Concomitant 
Diseases 
x 
 
 
 
 
 
 
 
Concomitant 
Medications 
x 
 
 
 
 
 
 
 
Glycemic 
Assessment 
Monitoring 
 
 
x 
 
 
 
x 
 
CGM Removal 
 
 
 
x 
 
 
 
x 
WHO Physical 
Activity 
Questionnaire 
x 
 
x 
 
x 
x 
 
x 
Food 
Record 
(Consumed 
Diet 
Assessment) 
x 
 
x 
x 
x 
x 
x 
x 
HbA1c Levels 
 
 
x 
 
x 
 
 
x 
Fructosamine 
 
 
 
 
x 
x 
 
 
Insulin Levels 
 
 
x 
 
x 
x 
 
x 

Oxidative 
Stress 
 
 
x 
 
x 
x 
 
x 
Inflammation 
Biomarkers 
 
 
x 
 
x 
x 
 
x 
Body 
Fat 
Quantification 
 
 
x 
 
x 
x 
 
x 
Nutritional 
Counseling 
and Food Plan 
 
 
 
x 
 
 
 
 
FP: Off-protocol, DP: On-protocol, MCG: Continuous Glucose Monitoring 
* Determination of HbA1c levels and BMI 
** Lipids (total cholesterol, HDL, LDLc, triglycerides), glucose, ALT, AST, creatinine, creatinine 
clearance, uric acid, albuminuria) 
Treatments (if applicable) (include a table for each study medication) 
Medication 1 
Item 
Include 
corresponding 
information 
No Not 
applicable 
Name 
Dapagliflozin 
 
 
Does it comply with "Good Manufacturing 
Practices"? 
Yes 
 
 
Codes, labeling, storage, retention, and 
safeguarding of drug samples 
Yes 
 
 
Pharmaceutical form 
Tablets of 10 mg  
 
 
Dose 
1 tablet 
 
 

Administration interval 
Every 24 hours 
 
 
Route of administration 
Oral 
 
 
Administration speed 
Immediate, with a glass of 
water 
 
 
Duration of treatment 
12 weeks 
 
 
Medication 2 
Item 
Include 
corresponding 
information 
No Not 
applicable 
Name 
Metformin 
 
 
Does 
it 
comply 
with 
"Good 
Manufacturing Practices"? 
Yes 
 
 
Codes, labeling, storage, retention, and 
safeguarding of drug samples 
Yes 
 
 
Pharmaceutical form 
Tablet 1000 mg 
Tablet 500 mg 
 
 
Dose 
1 tablet of 1000 mg or 2 
tablets of 500 mg  
 
 
Administration interval 
Every 12 hours 
 
 
Route of administration 
Oral 
 
 
Administration speed 
Immediate, with a glass of 
water 
 
 
Duration of treatment 
12 weeks 
 
 

Follow-up 
Item 
Include corresponding information 
No Not 
applicable 
Number of study 
phases 
2 
 
 
Number 
of 
visits 
and 
scheduling 
(include times) 
8 
Patient visits will be scheduled in the morning, from 
8 am to 12 pm, ensuring that appointments during 
the study occur at the same time for each patient. 
 
 
Duration of each 
study phase 
Phase 1, pre-randomization: 2 weeks.  
Phase 2, treatment: 12 weeks 
 
 
Laboratory 
and 
imaging studies 
HbA1c, insulin, fructosamine, lipid profile, uric acid, 
serum creatinine, urinary creatinine, serum albumin, 
urinary microalbumin, inflammation markers, and 
transaminases. 
 
 
Total duration of 
follow-up 
13 weeks 
 
 
Sampling methods 
Randomisation 
 
 
Treatment options 
offered at the end of 
the study 
Standard glucose lowering medication 
 
 
Overdose Management 
● Metformin: In cases of overdose, gastric lavage and supportive measures according to 
symptoms will be performed, with close monitoring every 4 hours until clinical resolution. 
● Dapagliflozin: Due to its mechanism of action, dapagliflozin very rarely causes 
hypoglycemia even at doses up to 50 times that used in this study. However, in case of 

overdose, appropriate supportive treatment will be provided as indicated by the patient's 
clinical status, with close monitoring every 4 hours until clinical resolution. 
Rescue Therapy 
According to the ADA/EASD 2019 guidelines [49], at 12 weeks, it will be assessed whether the 
patient reaches HbA1c targets. If the individualized target is not met, or if the patient has fasting 
glucose > 140 mg/dL at any visit, rescue therapy will be administered: 
● Group 1: Dapagliflozin 10 mg/day + Metformin 2000 mg/day + glimepiride or glibenclamide 
or gliclazide or glipizide. 
● Group 2: Metformin 2000 mg/day + glimepiride or glibenclamide or gliclazide or glipizide.  
 
If the patient has postprandial glucose > 180 mg/dL on capillary blood glucose monitoring at 
home, rescue therapy will be added: 
● Group 1: Dapagliflozin 10 mg/day + Metformin 2000 mg/day + glimepiride or glibenclamide 
or gliclazide or glipizide. 
● Group 2: Metformin 2000 mg/day + glimepiride or glibenclamide or gliclazide or glipizide. 
 
Permitted Concomitant Therapies 
Medications for concomitant medical conditions will be permitted. However, caution should be 
taken when using the following drug groups, given their interaction with Metformin: 
● Drugs that may adversely affect renal function, which may increase the risk of lactic acidosis, 
e.g., NSAIDs, including selective cyclooxygenase (COX) II inhibitors, ACE inhibitors, 
angiotensin II receptor antagonists, and diuretics, especially loop diuretics. Standardized 
medications and dose ranges will be established to homogenize the sample as much as 
possible. 
● In case of elevated blood pressure, Losartan will be administered, titrating the dose based 
on response, always within ranges of 25-100 mg/day. 
● In patients with dyslipidemia, Rosuvastatin 2.5-40 mg/day will be preferred. 
● In case of elevated triglycerides, the preferred therapy will be Bezafibrate 50-600 mg/day. 
● Elevated uric acid levels will be managed with Allopurinol at doses of 100-300 mg/day, dose-
response. 
● In case of newly diagnosed hypothyroidism, the Levothyroxine dose will be calculated at 1.6 
μg/kg/day. 

● For patients already under treatment for any previously mentioned conditions, the same 
management will continue and will be noted in the analysis section. 
● For patients experiencing pain, fever, or needing non-steroidal anti-inflammatory drugs, 
Paracetamol 2-3 g/day will be the administered.  
Condition 
Medication and Dose 
Hypertension 
Losartan 25-100 mg/day 
Hypercholesterolemia Rosuvastatin 2.5-40 mg/day 
Hypertriglyceridemia 
Bezafibrate 50-600 mg/day 
Elevated uric acid 
Allopurinol 100-300mg/day 
Hypothyroidism 
Levothyroxine at 1.6 μg/kg/day 
Pain, fever 
Paracetamol 2-3g/day 
*The exact dose will be defined using the dose-response method and adjusted to each patient's 
requirements. 
Prohibited Concomitant Therapies 
● Medications with intrinsic hyperglycemic activity (e.g., glucocorticoids (systemic and local) 
and sympathomimetics). 
● Organic Cation Transporters (OCT). Metformin is a substrate of OCT1 and OCT2 
transporters. 
○ Co-administration of Metformin with: 
■ OCT1 inhibitors (like verapamil) may reduce the efficacy of Metformin. 
■ OCT1 inducers (like rifampicin) may increase gastrointestinal absorption and 
efficacy of Metformin. 
■ OCT2 inhibitors (like cimetidine, dolutegravir, ranolazine, trimethoprim, vandetanib, 
isavuconazole) may decrease Metformin elimination, potentially increasing plasma 
Metformin concentration. 
■ Inhibitors of both OCT1 and OCT2 (like crizotinib, olaparib) may alter efficacy and 
renal elimination of Metformin. 

● Relevant considerations will be taken according to the approved prescribing information for 
the product. 
Definition of Follow-up Variables 
● Primary Variable: Change from baseline in GV (MAGE) in mg/dL after 12 weeks of 
treatment between the DAPA+ MET group versus the MET monotherapy group. 
● Secondary Variables: 
○ Change from baseline (absolute difference) in HbA1c levels (%) after 12 weeks of 
treatment between the DAPA + MET group versus the MET monotherapy group. 
○ Change from baseline (total difference) in insulin levels (µU/mL) after 12 weeks of 
treatment between the DAPA + MET group versus the MET monotherapy group. 
○ Change from baseline (absolute difference) in oxidative stress measurement (total 
antioxidant capacity) after 12 weeks of treatment between the DAPA + MET group 
versus the MET monotherapy group. 
○ Change from baseline (total difference) in the measurement of inflammation biomarkers 
(VCAM-1 and adiponectin) after 12 weeks of treatment between the DAPA + MET group 
versus the MET monotherapy group. 
○ Change from baseline (absolute difference) in body fat quantification after 12 weeks of 
treatment between the DAPA + MET group versus the MET monotherapy group. 
○ Change from baseline (total difference) in the parameters of cardio-metabolic risk factors 
(weight (kg), total cholesterol (mg/dL), HDL (mg/dL), LDLc (mg/dL), albuminuria (mg/mg 
creatinine), and blood pressure (mmHg)) after 12 weeks of treatment between the DAPA 
+ MET group versus the MET monotherapy group. 
Methods for Data Collection 
Electronic Record containing the clinical history collected via telemedicine (Phone call/Videocall, 
Whatsapp, Teams, Zoom or Google Forms), information gathered at each visit, notes containing 
patient physical examinations, physical activity questionnaires answered via telemedicine (Phone 
call/Videocall, Whatsapp, Teams, Zoom or Google Forms), Nutrition notes collected via 
telemedicine (Phone call/Videocall, Whatsapp, Teams or Zoom), and laboratory results. Patients 
will only be identified by their initials, date of birth, and the internal protocol folio number. 
 
Monitoring and Auditing Procedures During Study Development 
Not applicable 

Criteria for Failure and Success 
● Failure: No decrease in GV in the DAPA + MET group compared to the MET monotherapy 
group. 
● Success: A decrease in GV in the DAPA+ MET group compared to the MET monotherapy 
group. 
Sample Size  
The sample size was determined using the difference of means formula: 
n = (Zα / 2 + Zβ) 2 * 2 * σ2 / d2,  
A reduction in glucose variability from 4.85 to 2.2 was estimated with an expected standard 
deviation of 2.8 in the MAGE index (values based on the study by R. R. Henry et al., “Effects of 
Dapagliflozin on 24-Hour Glycemic Control in Patients with Type 2 Diabetes: A Randomized 
Controlled Trial,” Diabetes Technol. Ther., vol. 20, no. 11, pp. 715–724, Nov. 2018.), with an alpha 
value of 0.05 and a power of 0.80, resulting in a sample size of 88 subjects, with 44 subjects in 
each treatment group. No adjustments were included in the sample size calculation to estimate 
the subjects required for the estimated differences in secondary variables. 
 
Description of techniques, devices, and/or instruments to be used (Including special mechanical, 
electronic, cybernetic equipment) 
 
Continuous glucose monitoring will be performed using the iPro™2 Continuous glucose monitor, 
from Medtronic®, to determine the MAGE value as follows: 
● Calculation of Mean Amplitude of Glucose Excursion (MAGE): 
○ In the first step, all local maximum/minimum values are determined. 
○ The next step is an evaluation of maximum/minimum pairs against the standard deviation 
(SD). 
○ If the difference from minimum to maximum is greater than the SD, this variation from 
the mean measurement is retained. 
○ If the local maximum/minimum is less than 1 SD, it is excluded from further calculations. 
○ These channels are retained and summed to achieve the MAGE 
● Glycated hemoglobin (HbA1c) will be measured using HPLC (Variant II Turbo, Biorad). 
● Insulin levels will be measured with Access-2 equipment (Beckman Coulter, Inc.). 
● Oxidative stress will be measured with the BioAssay Systems antioxidant assay kit (DTAC-

100) (QuantiChrom Antioxidant Assay Kit) (BioAssay Systems). 
● VCAM-1 will be measured using ELISA kits (Merck Millipore, USA). 
● Adiponectin measured using ELISA kits (Merck Millipore, USA). 
● Body fat quantification by bioelectrical impedance with the Jawon scale, model5 IOI 353 - 
JMW160. 
● Anthropometric variables will be measured using standardized techniques; these include 
height, weight, waist, and hip circumferences. 
● BMI will be calculated using the equation: weight / height² (kg/m2). 
● Blood pressure will be measured considering the mean of two determinations after sitting for 
at least 5 minutes. 
● Mean arterial pressure (MAP) will be calculated with the formula: (systolic blood pressure * 
0.33) + (diastolic blood pressure * 0.66). 
● After at least eight hours of fasting, glucose, lipid profile (total cholesterol (mg/dL), HDL 
(mg/dL), LDL (mg/dL), triglycerides (mg/dL)), creatinine (mg/dL), uric acid (mg/dL), alanine 
aminotransferase (ALT) (U/L), aspartate aminotransferase (AST) (U/L) will be measured 
using the Unicell Dxc600 analyzer (Beckman Coulter, Inc.). 
● Albuminuria will be measured using the Unicell Dxc600 analyzer (Beckman Coulter, Inc.). 
● Exosome quantification: a 30ml urine sample is collected. Protease inhibitors are 
immediately added to this urine, and it is stored at -80°C. For exosome extraction, the urine 
is thawed on ice and vigorously shaken to re-homogenize it. A total of 8 ml is taken and 
centrifuged at 17,500 g for 15 minutes at 4°C to remove sediments. From this procedure, the 
supernatant (1) will be isolated into a clean tube, and the pellet (1) will be processed with 
200mg/ml of dithiothreitol (DTT) dissolved in a volume of 100μl of isolation solution (10mM 
triethanolamine and 250mM sucrose at pH 7.6), incubated for 5 minutes at 37°C, and 
subsequently centrifuged at 17,500 g for 10 minutes at 37°C. From this procedure, 
supernatant 2 will be obtained and mixed with supernatant 1, while pellet (2) will be 
discarded. The supernatant mixture is centrifuged at 200,000 g for 2 hours at 4°C, the 
supernatant (3) is discarded by decantation, and the pellet (3) is dissolved in 50μl of lysis 
buffer with phosphatase inhibitors and will be analyzed via Western Blot. 
● LDL Cholesterol will be estimated using the Friedewald equation (LDL = total cholesterol - 
HDL - triglycerides / 5) [23]. 
● Creatinine clearance will be calculated using the CKD-EPI equation. 
● A WHO physical activity questionnaire will be administered. 
● A food record sheet will be completed at each visit. 

● All samples will be measured in the Laboratory of the Department of Endocrinology and 
Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán 
(http://www.innsz.mx/opencms/contenido/departamentos/labcentral/). 
In 
the 
case 
of 
analytes whose processing is not immediate or within the first few days, the sample will be 
preserved by ultra-freezing (-70°C) until processing. 100% of the samples are certified by 
the College of American Pathologists (71893-07-01). 
Description of evaluation formats, questionnaires, checklists, etc., indicating validity, 
reproducibility criteria, and quality controls  
Not applicable 
 
Does the protocol involve the handling and labeling of biological samples? If applicable, mention 
the procedures that will be used 
 
Yes, with the patient's initials, date of birth, internal laboratory patient number, and randomization 
number. 
 
Information to ensure that obtained biological samples will not be used for permanent or immortal 
cell lines or purposes unrelated to the study 
 
Qualified personnel will take samples for this activity and will be processed within the institution. 
Samples will not be sent to any other institution/company, so there is no risk of being used for 
purposes other than those stipulated in the protocol. 
 
Description of treatment groups 
Included subjects will be randomized 1:1 to receive: 
● Group 1: Dapagliflozin 10 mg/day + Metformin 2000 mg/day and, if necessary, as mentioned 
previously, rescue treatment. 
● Group 2: Metformin 2000 mg/day and, if necessary, as mentioned previously, rescue 
treatment. Treatments will be administered for 12 weeks. Patients who do not tolerate 
Metformin at a dose of 2000 mg will have their dose adjusted to 1500 mg daily. If patients do 
not tolerate 1500 mg daily, the dose will be titrated to 1000 mg daily. If they do not tolerate 
this dose, they will be withdrawn from the study. 

Mechanisms for treatment assignment 
The https://www.google.com/search?q=randomization.com tool will be used (The Table is 
attached as Appendix 1 of the protocol). 
 
If a placebo group is used, include its justification 
Not applicable 
 
Criteria for premature withdrawal from the study 
● Allergic reaction to any of the study medications or their excipients. 
● Patients who do not tolerate Metformin 1000 mg/day. 
● Severe life-threatening illness. 
● Pregnancy during the study. 
● Presence of acute renal failure (decrease in > 40% of glomerular filtration rate). 
● Lactic acidosis or ketoacidosis. 
Procedures for withdrawing a patient from the study 
The patient will be notified of withdrawal from the protocol and will receive standard treatment, 
according to AACE 2019 guidelines (MET, GLP1 agonist, SGLT2 inhibitor, DPP4i, acarbose, 
thiazolidinediones, insulin, or sulfonylurea) and will be referred for follow-up at the secondary care 
level. 
Criteria for premature (partial or complete) suspension of the study 
NA 
 
Selection Criteria 
a) Inclusion criteria  
● Subjects > 18-77 years old. 
● Both men and women. 
● HbA1c ≥ 7.7% <12% (HbA1c from 9 to <12%: without catabolic symptoms). 
● BMI > 25 kg/m2. 
● Diagnosis of T2D: if a patient has taken any drug and/or insulin,  they will be prescribed only 
Metformin as a washout period in the pre-randomization phase for 2 weeks.  
b) Exclusion criteria 
● Complications related to T2D and catabolic symptoms. 
● HbA1c >9% with catabolic symptoms. 

● CKD-EPI creatinine clearance: <60 ml/min. 
● LADA or T1D. 
● Concomitant clinically significant disease such as: liver, hematological, oncological, 
psychiatric, or rheumatic disease. 
● Symptoms of markedly uncontrolled diabetes: (marked polyuria or polydipsia + 10% weight 
loss within the last 3 months before enrollment). 
● Known hypersensitivity to dapagliflozin, metformin, or any of the drug excipients. 
● Unstable or rapidly progressing kidney disease. 
● Patients with severe liver failure (Child-Pugh class C). 
● Patients with bariatric surgery. 
● Any major CV event / vascular disease within 3 months before signing consent at enrollment, 
as assessed by the investigator. 
● For women only: currently pregnant (confirmed with a positive pregnancy test) or lactating. 
● Being hospitalized or having less than one month since hospital discharge.  
c) Elimination criteria 
● Allergy to dapagliflozin, severe life-threatening illness, or pregnancy during the study. 
● Patients presenting with acute renal failure (decrease in > 40% of GFR) 
● For women only: pregnancy confirmed with serum chorionic gonadotropin. In case of 
pregnancy during the study, the subject must be eliminated from the trial, offered standard 
treatment indicated in point 36, and the Pregnancy Outcome Report (Annex) must be 
completed to record essential details of the mother. Part I should be completed after 
pregnancy identification and Part II is to record the pregnancy outcome. 
39. Outcomes and Variables 
● Primary Variable: Change from baseline in GV (MAGE) in mg/dL after 12 weeks of 
treatment between the DAPA+ MET group versus the MET monotherapy group. 
● Secondary Variables: 
○ Change from baseline (absolute difference) in HbA1c levels (%) after 12 weeks of 
treatment between the DAPA + MET group versus the MET monotherapy group. 
○ Change from baseline (total difference) in insulin levels (µU/mL) after 12 weeks of 
treatment between the DAPA + MET group versus the MET monotherapy group. 
○ Change from baseline (absolute difference) in oxidative stress measurement (total 
antioxidant capacity) after 12 weeks of treatment between the DAPA + MET group 
versus the MET monotherapy group. 

○ Change from baseline (total difference) in the measurement of inflammation biomarkers 
(VCAM-1 and adiponectin) after 12 weeks of treatment between the DAPA + MET group 
versus the MET monotherapy group. 
○ Change from baseline (absolute difference) in body fat quantification after 12 weeks of 
treatment between the DAPA + MET group versus the MET monotherapy group. 
○ Change from baseline (total difference) in the parameters of cardio-metabolic risk factors 
(weight (kg), total cholesterol (mg/dL), HDL (mg/dL), LDLc (mg/dL), albuminuria (mg/mg 
creatinine), and blood pressure (mmHg)) after 12 weeks of treatment between the DAPA 
+ MET group versus the MET monotherapy group. 
Methods to be used to contact patients 
Personal contact data such as landline and mobile phone numbers, email address will be obtained 
via Phone call/Videocall, Whatsapp, Teams, Zoom, or Google Forms. Due to the SARS-CoV-2 
pandemic, investigators will conduct home visits and/or collect data and hold medical 
consultations via Phone call/Videocall, Whatsapp, Teams, Zoom, or Google Forms. 
 
Statistical Analysis (Description of the information processing and presentation plan. Include 
justification for the statistical tests to be used) 
Stratified randomization in both groups to balance patient types and control potential bias. The 
normality of variables will be analyzed using the Kolmogorov-Smirnov test. According to the 
distribution of variables, they will be expressed as mean and standard deviation (SD) or median 
and interquartile range (IQR) for normally or skewed distributed variables, respectively. GV will 
be determined using the MAGE index. Comparison between the two groups will be evaluated 
using ANCOVA. A p-value based on two-tailed tests ≤0.05 will be considered significant. All 
analyses will be performed with SPSS 20.0 (Chicago, IL). Patients experiencing an acute stress 
event during the study will be excluded from the analysis due to the impact on GV. 
 
Justification of sample size (include study power and the p-value considered significant) 
The sample size was determined using the difference of means formula: 
n = (Zα / 2 + Zβ) 2 * 2 * σ2 / d2,  
A reduction in glucose variability from 4.85 to 2.2 was estimated with an expected standard 
deviation of 2.8 in the MAGE index, with an alpha value of 0.05 and a power of 0.80, resulting in 
a sample size of 88 subjects, with 44 subjects in each treatment group. No adjustments were 
included in the sample size calculation to estimate the number of subjects required for the 

estimated differences in secondary variables. 
 
Recruitment potential (number of subjects intended to recruit) 
It is estimated that approximately 15% of the subjects who start the project and enter the pre-
randomization period will not meet the criteria for the treatment period. Therefore, it is estimated 
that approximately 102 subjects will be assessed. 
 
If multicenter, include the global and local sample number 
Not applicable 
 
Procedures for reporting deviations from the original statistical plan 
A letter will be sent to the research committee for approval. 
 
Possible discomforts resulting from the study 
Frequency of follow-up visits, blood sample collection. 
 
Potential risks 
Those inherent to blood sampling. 
 
Methods for detecting anticipated risks 
Patients will be asked to report any side effects 24 hours a day. Patients will be able to contact 
the participating medical staff at any time. 
 
Safety measures for timely diagnosis and prevention of risks 
Patients reporting a side effect will be scheduled for evaluation. 
 
Procedures to follow to resolve risks if they occur 
Depending on the case, treatment for the complication or side effect will be provided, either with 
an outpatient prescription or the patient will be referred to the emergency department for 
assessment and treatment. Medical expense insurance will be available to cover treatment costs 
for patients associated with adverse effects secondary to the use of study medications. 
 
 
 

Expected direct benefits 
Patients who agree to participate in this research study will be comprehensively evaluated and 
more frequently compared to the standard treatment (see point 36) available at the time, giving 
the patient an advantage in better managing their disease. The additional tests performed could 
improve glucose control and also evaluate the function of other organs and systems. The 
medications administered during the study will lower blood glucose, thus, it is expected that 
microvascular complications will be prevented. Improvement in GV and control of plasma glucose 
levels will reduce the short-term risks associated with hypoglycemic episodes and the long-term 
risk of microvascular complications.  
 
Expected indirect benefits 
The study results may contribute to evaluating the impact of oral glucose-lowering medication on 
GV in Mexican patients with T2D who have significant glycemic dyscontrol. 
 
General risk-benefit assessment of the proposed study 
The oral glucose-lowering agents used in the study have potential risks such as hypoglycemia, 
gastrointestinal disorders, and increased frequency of urinary tract infections, which occur in only 
a small percentage of users, versus the benefit of controlling elevated glucose levels associated 
with micro and macrovascular complications. 
 
Specify costs (direct/indirect, monetary, time participation, visits/travel) generated by the research 
for the study subjects 
Patients must attend 8 visits, transportation costs will be covered by the study group.  
 
Specify whether consultations, laboratory/imaging tests, and medical/surgical treatments 
generated due to the study will be covered by the patient/research subject or not 
Expenses for emergencies or complications associated with the use of study medications will be 
covered by medical expense insurance. 
 
Report who will cover the costs associated with the research 
The study was designed by the principal investigator, without interference from the 
pharmaceutical industry. The project will receive financial support from AstraZeneca, which will 
provide dapagliflozin, consumables, and analysis costs, as well as publication fees. None of the 
research team members will receive financial compensation for their participation. 

If applicable, specify the incentives offered (incentive is understood as an offer or influence that 
compels an action without implying a significant deviation from our general life plan; e.g., giving 
a book for participating) 
Note: Compensation/incentive out of proportion is considered coercive. 
There will be no additional incentives for patients. 
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