ClinicalTrials.gov Identifier: NCT04090580 Registered on November 9th, 2019. https://www.clinicaltrials.gov/
This was a randomized, open-label, prospective, longitudinal, phase IV clinical trial that compared the use of DAPA + MET dual therapy versus MET SOC in subjects with newly diagnosed T2DM with an HbA1c between ≥ 7.5% to < 13.0% (≥ 64.4 and < 103.0 mmol/mol); a BMI > 25 kg/m2, no catabolic symptoms nor complications related to T2DM.
The study was an investigator-initiated study (IIS). AstraZeneca provided dapagliflozin tablets for subjects, and provided financial support for materials acquisition (CGM), and publication. The study was carried out in the Department of Endocrinology and Lipid Metabolism, at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ) with the authorization and approval of research ethics committees comprised of “Comisión de Ética en Investigación” in accordance with the declaration of Helsinki (local ethics committee authorization number REF 3089).
The primary objective of this study was to evaluate the effect of an early dual treatment of DAPA + MET versus MET for 12 weeks in GV in terms of ΔMAGE and ΔTIR%, in newly onset Mexican T2DM subjects.
The secondary objectives were to evaluate between groups: ΔBMI, Δweight, ΔHbA1c, Δglucose, Δinsulin, Δtotal cholesterol, ΔHDL-C, ΔLDL-C, Δtriglycerides, ΔALT, ΔAST, Δuric acid, Δserum creatinine, Δestimated glomerular filtration rate(eGFR), Δurinary albumin, body composition in terms of Δmuscle, Δfat, Δvisceral fat, Δacanthosis, Δskin tags, Δwaist, Δabdominal, Δwrist and Δneck circumferences; ΔSBP, ΔDBP, and Δpulse.
Our Hypothesis was that Newly onset Mexican T2DM subjects treated with DAPA + MET would show a significant lower GV, compared to subjects with MET SOC.
We followed these selection criteria: age: 18–77 years, both men and women, HbA1c ≥ 7.5% and < 13.0%, BMI > 25 kg/m2 and newly onset T2DM diagnosis.
The exclusion criteria were: HbA1c ≥ 13.0%, insulin treatment, T2DM-related complications and/or any catabolic symptoms, HbA1c > 9.0% (> 77.2 mmol/mol) with catabolic symptoms, CKD-EPI creatinine clearance: <60 mL/min, LADA or T1 diabetes, clinically significant concomitant disease such as: hepatic, hematological, oncological, psychiatric or rheumatic disease, symptoms of marked uncontrolled diabetes: (marked polyuria or polydipsia + 10% weight loss prior to last 3 months of enrollment), known hypersensitivity to DAPA or MET, unstable or rapidly progressing kidney disease, severe hepatic impairment (Child-Pugh class C), bariatric surgery, major CV event / vascular disease within 3 months prior to consent signing at enrollment, as assessed by investigator and/or being hospitalized or having less than a month of hospital discharge. Women who were pregnant confirmed by pregnancy test with serum chorionic gonadotropin or lactating.
The elimination criteria were: if any patient developed allergy to DAPA, any severe life-threatening illness, acute renal failure (> 40% decrease in eGFR), patients who could not tolerate at least 1000 mg of MET per day. Women confirmed pregnancy by test with serum chorionic gonadotropin, lactating or desire to lactate.
The sample size was determined using the mean difference formula: n = (Zα / 2 + Zβ) 2 * 2 * σ2 / d2 a reduction in GV was estimated from 4.85 to 2.2 with an expected standard deviation of 2.8 in the MAGE index according to RR. Henry et al. [19]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.
Patient recruitment began in October 2019 and was interrupted due to the SARS-COV-2 pandemic in March 2020. Nevertheless, patients who were already enrolled were followed up. Recruitment was normally restarted in March 2021; one of the inclusion criteria was adjusted, allowing HbA1c < 13.0%, prior limit < 12.0%. The last patient was recruited on December 6th, 2021.The complete study was concluded in March 2021.
A total of 88 patients met the selection criteria, signed the informed consent, and were randomized 1:1 on www.randomization.com (complete list of it is showed as supplementary material) to receive daily either DAPA 10 mg + MET 2000mg or MET 2000mg for 12 weeks. Both groups were monitored for GV using a CGM system for 7 days at baseline (W0) and on week 12 (W12).
Pre-randomization: patients were given 2000mg of MET daily for two weeks, only patients who tolerated this dose were included in the study and a treatment was randomly assigned.
Treatment: subjects who met the pre-randomization period and tolerated treatment were randomized 1:1 to receive either DAPA 10 mg/day + MET 2000 mg/day or MET 2000 mg/day for 12 weeks.
Of the total of 264 patients surveyed, a sample of 88 met the inclusion criteria and none of the exclusion criteria randomization DAPA + MET n = 42 and MET n = 46. During the study, 7 patients discontinued (DAPA + MET n = 1 and MET n = 6). 80 patients concluded the study for 12 weeks (DAPA + MET n = 41 and MET n = 39). One patient was removed from the study (MET n = 1) because he did not comply his medication intake nor the instructions during CGM. Study flowchart is displayed in Fig. 1.
The baseline characteristics were, the age [53.7 ± 8.6 years DAPA + MET versus 50.9 ± 11.8 years MET; p = 0.2], TIR% Target: 70–180 mg/dL [55.5% (12.6–80.6) DAPA + MET versus 82.7%(26.1–95.1) MET; p = 0.02], BMI [30.9 ± 6.9 kg/m2 DAPA + MET versus 30.1 ± 3.2 MET; p = 0.24], glucose [202.4 ± 70.5 mg/dL DAPA + MET) versus 179.0 ± 62.9 mg/dL MET; p = 0.11], insulin [12.2 ± 13.3 µU/mL DAPA + MET versus 10.9 ± 6.6 µU/mL MET; p = 0.57]. Complete baseline characteristics of the subjects included are summarized in Table 1.
Table 1
Baseline Characteristics of the subjects included (n = 88)
| DAPA + MET n = 42 | MET n = 46 | p |
age years | 53.7 ± 8.6 | 50.9 ± 11.8 | 0.200 |
women | 22 (52.4%) | 23 (50.0%) | 0.460 |
MAGE mmol/L | 4.3 ± 1.2 | 4.1 ± 1.5 | 0.404 |
TIR% very high > 250 mg/dL | 2.9 (0.4–24.4) | 1.6 (0.0–14.0) | 0.127 |
TIR% high > 180 mg/dL | 36.1 (12.6–54.2) | 15.8 (0.4–47.7) | 0.038 |
TIR %target 70–180 mg/dL | 55.5 (12.6–80.6) | 82.7 (26.1–95.1) | 0.026 |
TIR% low < 70 mg/dL | 0 (0–0) | 0 (0.0-0.2) | 0.337 |
TIR% very low < 54 mg/dL | 0 (0–0) | 0 (0–0) | 0.606 |
BMI kg/m2 | 30.9 ± 6.9 | 30.1 ± 3.2 | 0.240 |
weight kg | 81.3 ± 19.1 | 80.0 ± 13.9 | 0.710 |
HbA1c% | 9.2 ± 1.6 | 9.4 ± 1.3 | 0.920 |
glucose mg/dL | 202.4 ± 70.5 | 179.0 ± 62.9 | 0.110 |
insulin µU/mL | 12.2 ± 13.3 | 10.9 ± 6.6 | 0.570 |
total cholesterol mg/dL | 212.8 ± 53.3 | 191.4 ± 39.5 | 0.030 |
HDL mg/dL | 43.1 ± 9.0 | 41.5 ± 8.8 | 0.390 |
LDL mg/dL | 121.6 ± 39.5 | 106.0 ± 32.8 | 0.120 |
triglycerides mg/dL | 193.0 (135.2-271.2) | 185.5 (135.2–240.0) | 0.429 |
ALT U/L | 29.0 (22.7–41.0) | 36.5 (25.5–64.5) | 0.037 |
AST U/L | 23.0 (19.7–30.5) | 29.5 (23.0-43.7) | 0.013 |
uric acid mg/dL | 5.7 ± 1.3 | 5.4 ± 1.4 | 0.370 |
serum creatinine mg/dL | 0.74 ± 0.20 | 0.72 ± 0.18 | 0.710 |
eGFR mL/min/1.73 m2 | 98.4 ± 16.5 | 102.5 ± 14.3 | 0.240 |
urinary albumin mg/dL | 5.1 ± 5.6 | 3.7 ± 6.1 | 0.390 |
muscle % | 28.4 ± 6.5 | 27.0 ± 5.5 | 0.280 |
fat % | 37.0 ± 9.0 | 37.5 ± 8.8 | 0.780 |
metabolic age years | 62.8 ± 9.2 | 61.7 ± 9.3 | 0.580 |
visceral fat % | 12.3 ± 4.1 | 13.1 ± 5.3 | 0.430 |
acanthosis % | 100% | 100% | 0.010 |
skin tags % | 100% | 100% | 0.710 |
neck circumference cm | 39.6 ± 3.6 | 40.8 ± 4.1 | 0.140 |
waist circumference cm | 100.9 ± 11.7 | 100.6 ± 8.7 | 0.910 |
abdominal circumference cm | 104.7 ± 13.2 | 105.8 ± 15.6 | 0.730 |
wrist circumference cm | 16.9 ± 1.0 | 16.9 ± 1.0 | 0.920 |
SBP mm/Hg | 136.1 ± 21.8 | 130.8 ± 16.6 | 0.200 |
DBP mm/Hg | 81.5 ± 11.7 | 81.5 ± 9.0 | 0.990 |
pulse bpm | 72.5 ± 9.1 | 71.2 ± 6.6 | 0.450 |
All the measurements were carried out fasting. Student's T test was performed for normal variables to obtain mean and significance. Non-normal variables are expressed with mean interquartile values of 25% and 75%, and significance was obtained with the Mann Whitney U test. |
All the measurements were carried out fasting. Student's T test was performed for normal variables to obtain significance. Skewed distribution variables are expressed with median and interquartile values of 25% and 75%, significance for these variables was obtained with the Mann Whitney U test.
An isocaloric diet was indicated, taking as reference the calories consumed in the 24-hour recall. The macronutrient distribution was 40% carbohydrate, 20% proteins, and 40% lipids.
Subjects used a CGM for 7 days at baseline (W0), before being assigned any treatment and during the last week of intervention (W12). The iPro™ CGM system (Medtronic, Northridge, CA) was used.
If a patient presented fasting glucose > 140 mg/dL (> 7.7 mmol/L) at any visit, rescue therapy (glimepiride 2mg) was added independently of the assigned group of the study.
Medtronic's iPro™ CGM (n = 44) system was discontinued in September 2021, so MiniMed™ 640G Insulin Pumps with blinded screens (n = 44), and “enlite” sensors, the same as those used with iPro, were used, so VG could be monitored in the same way in all patients with sensors of the same brand, only with slightly different recording data devices.
Due to the COVID-19 pandemic questionnaires were done digitally, and some sessions were done virtually, all patients had insurance for major medical expenses and an emergency telephone number to which they could communicate at any time was provided.