A Comparison of Efficacy among Syrian diabetic patients treated with Empagliflozin versus Dapagliflozin, a Randomized, Triple-blind,

Two-period crossover study

 

Nihad Kharrat Helu*, Abdulhakim Nattouf

Clinical Pharmacy and Hospital Pharmacy, Pharmaceuticals and Pharmaceutical Industry Department,

College of Pharmacy, Damascus University, Syria.

 

ABSTRACT:

Objective: To directly compare the effectiveness of the highest approved doses of two sodium-glucose co-transporter 2 (SGLT2) inhibitors Empagliflozin and Dapagliflozin as part of Dual oral antidiabetic agents in type 2 diabetes (T2DM) patients. Methods: This study was a randomized, triple-blind, crossover, 24-week monocenter Trial. T2D Patients were randomized to receive metformin 1000mg b.i.d with Empagliflozin 25 mg/day and then metformin 1000mg b.i.d with Dapagliflozin 10mg/day (n=24) or vice versa (n=23). Each treatment period was 12 weeks with a 10-day washout period in between (without stopping metformin). The parameters evaluated at baseline and after 12 and 24 weeks. The primary outcome was the mean change from baseline in haemoglobin A1c (HbA1C), Fasting Blood Glucose (FBG), Body Mass Index (BMI), Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP). Analyses were done per the Per-protocol principle. Results: Empagliflozin administration showed significant reductions in HBA1C, FBG, BMI, SBP and DBP (p>0.05), Dapagliflozin administration improved the levels of HBA1C, FBG, BMI, SBP and DBP but it was significant only in FBG (p=0.001) and SBP (p=0.035). There were no significant changes from baseline in HbA1c, FBG, SBP and DBP with Empagliflozin treatment compared with Dapagliflozin (P<0.05). Both groups showed reductions in BMI but the reduction was greater in the Empagliflozin group (between groups; p=0,044). Conclusions: This study showed that SGLT2 inhibitors can be effectively used as dual oral antidiabetic agents in T2D patients who are treated with metformin. More specifically, Empagliflozin was more effective in reducing BMI.

 

 

 

INTRODUCTION: 

Type 2 Diabetes Mellitus (T2D) is a chief global public health concern. About half a billion people are living with diabetes worldwide and the number is increasing¹. The chronic stage of hyperglycemia is related to the continuous impairment of eyes² and sexual dysfunction³. Diabetes is an important risk factor for Cardiovascular death⁴ and coronary heart disease⁵. In many recent studies, a number of new treatments to control blood glucose have been presented, and new ways to use of older treatments have been developed.

 

There are many distinct classes of hypoglycemic agents existing, each class show distinctive pharmacologic properties. And many studies have described recent nanotechnology research in the detection of insulin and blood sugar by implantable sensor and microphysiometer and the latest stem cell research that occurs in diabetes treatment in addition to the beneficial use of natural formulations for better management of diabetes mellitus^6–9. However, there is a remaining unmet need for new glucose-lowering therapies that provide durable glycemic control while avoiding hypoglycemia, weight gain and fluid retention, which are documented problems with several existing glucose-lowering drugs^10,11.

 

 

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a novel class of anti-diabetic medication that aims to improve glucose control by increasing renal glucose excretion by suppressing SGLT2 function in the kidneys¹². SGLT2 inhibitors decrease the fasting plasma glucose (FPG) and postprandial (PPG) in addition to reducing body weight via secondary caloric loss due to urinary glucose excretion^13,14. SGLT2 inhibitors reduce blood pressure by promoting osmotic diuresis¹⁵. To date, there is no data on the use of SGLT2 inhibitors in Syria. Empagliflozin and Dapagliflozin are orally active and potent inhibitor of SGLT2. Previous randomized controlled trials reported that Empagliflozin is effective as a mono therapeutic medication¹⁶ or add to metformin therapy^17,18. Dapagliflozin, as well, has been reported to be effective as mono therapeutic medicine^19–21 or add to metformin therapy^22–24. Most previous studies have only reported the efficacy and safety of each medicine or its network meta-analysis results. To date, however, there are no direct clinical studies that have compared the efficacy of Empagliflozin and Dapagliflozin As adding to metformin therapy in T2D patients.

 

MATERIALS AND METHODS:

Study Population:

The inclusion criteria were age >18 years, type 2 diabetes with a haemoglobin A1c (HbA1c) level >7%, BMI >18.5. The exclusion criteria included type 1 diabetes, past ketoacidosis, using Insulin, possible or actual pregnancy or nursing estimated glomerular filtration rate [eGFR] <60mL/min/1.73m² and any patient judged by the investigator to be inappropriate for this study. Using any anti-diabetic drug was prohibited within 10 days before randomization. All patients had visited the Department of Endocrinology at Arbeen Medical Center. This study protocol was approved by an ethics committee/institutional review board of Damascus University. All procedures were conducted per the Helsinki Declaration and the International Conference of Harmonization/Good Clinical Practice guidelines. All patients provided written informed consent before participation.

 

Study Design:

This was a randomized, triple-blind, two-period crossover study (24-weeks, each treatment period lasted 12weeks with a 10-day washout period to avoid carryover effects.). Each participant underwent a baseline phase (10 days), participants were not counseled to adhere to a specified at-home diet. participants were randomized to one of two treatment sequences, AB or BA as follows: The AB group received Empagliflozin 25mg with metformin 1000mg b.i.d for the first 12 weeks and Dapagliflozin 10mg with metformin 1000mg b.i.d for the following 12 weeks. The BA group received Dapagliflozin 10mg with metformin 1000mg b.i.d for the first 12 weeks and Empagliflozin 25mg with metformin 1000mg b.i.d for the following 12 weeks. No changes were made to the types and doses of glucose-lowering drugs and drugs for commitment illnesses during the study period to avoid possible effects on the outcomes. The Dapagliflozin and Empagliflozin tablets appeared identical and were supplied in identical bottles to ensure blinding treatment. Empagliflozin tablets used in the present study were manufactured and provided by (City Pharma Pharmaceuticals, Damascus, SY; batch number 4277). Dapagliflozin tablets were manufactured and provided by (Al-Fares Pharmaceuticals, Damascus, SY; batch number 006).

 

Endpoints and Assessments:

The primary endpoints in this study were calculated by subtracting the 12 weeks from baseline values in each period of the two periods of the study. The primary values were designated as mean changes in (1) HbA1c; (2) FPG; (3) BMI; (4) SBP and (5) DBP.

 

At baseline, each patient medical history, onset age of diabetes, weight, commitment drugs were noted. data as SBP, DBP, bodyweight and laboratory data were measured at baseline, 12 and 24weeks, respectively. telephone calls were made to participants to assess tolerability.

 

Participants were taught to have their study medication in the morning; on study appointment days, medication was taken after the appointment. At each study visit, a physical examination was done, patient’s bodyweight and blood pressure were measured. The mean of the three measurements which were measured for Blood pressure (systolic and diastolic) was used in the analysis. Blood samples were taken in fasted condition. HbA1c was measured using Immunofluorescence Assay by the I-chroma HbA1c analyzer (Boditech MED., INC., Korea. LOT: AAPXE27.). FBG was measured using the GLUC-PAP analyzer (Randox Laboratories Ltd, United Kingdom).

 

Statistical Analysis:

Descriptive statistics were used for baseline characteristics, which were summarized as means and ± standard deviations or numbers of subjects. The analysis was performed according to the per-protocol principle, including all available measurements. The Shapiro-Wilk test for normality was examined for the appropriate statistical test for continuous variables. Differences between continuous variables were analyzed using a paired t-test, unpaired t-test, Mann–Whitney test, or Wilcoxon Signed Ranked Test, as appropriate. A P value <0.05 was considered statistically significant. All analyses were performed using SPSS version 25.0 (IBM Corp., Armonk, NY, USA).

RESULTS:

Patients characteristics:

85 patients were screened between Oct 2019 and Oct 2020 only 47 met the inclusion criteria and were enrolled and randomly assigned to receive Metformin 1000mg b.i.d and Empagliflozin 25 mg for 12 weeks then Metformin 1000mg b.i.d and Dapagliflozin10mg per day for 12 weeks (n=24) or vice versa (n=23). Of the 47 patients initially enrolled in the study, 37 completed the 24-week period. 5 were lost to follow up, 3 didn't show treatment commitment and 2 experienced side effects (figure 1). All patients had at baseline (mean HbA1C 9.65 and 9.90, mean FBG 241.92 and 240.97, mean BMI 30.30 and 29.78, mean SBP/DBP 141.22/87.43 and 138.24/ 83.78 for Empagliflozin and Dapagliflozin, respectively. The patients’ clinical demographic and baseline characteristics were balanced between A and B groups (table 1) baseline characteristics for AB, BA and all patients are described in (table 2).

 

Figure 1. Study flowchart.

 

Table 1: Baseline clinical parameters of study participants (Empagliflozin and Dapagliflozin groups):

HBA1C: Hemoglobin A1C, FBG: fasting blood glucose, BMI: body mass index, SBP: systolic blood pressure, DBP: diastolic blood pressure. variables were analyzed using paired T-test or Wilcoxon Signed Ranked Test.

 

Table 2: Baseline demographics and clinical parameters of study participants:

Variables	Overall (n=37)	Group AB (n=19)	Group BA (n=18)	P-value
Age, years	55±8	57±8	53±8	0.118
Sex, n(%) Female Male	28 (75.7%) 9 (24.3%)	18 (94.7%) 1 (5.3%)	10 (55.6%) 8 (44.5%)	* *
Weight, kg	72.81±10.839	74.37±10.264	80.00±8.718	0.081
HBA1C, %	10.41±2.44	10.28±2.23	10.54±2.72	0.808
FBG, mg/dL	270.11±102.84	278.53±104.43	261.22±103.36	0.564
BMI, Kg/m2	30.95±3.32	30.68±3.80	31.23±2.79	0.617
SBP, mmHg	145.00±21.73	147.63±25.08	142.22±17.84	0.226
DBP, mmHg	86.89±11.57	89.77±13.07	83.89±9.16	0.491

HBA1C: Hemoglobin A1C, FBG: fasting blood glucose, BMI: body mass index, SBP: systolic blood pressure, DBP: diastolic blood pressure. Continuous variables were analyzed using Independent t-tests or Mann–Whitney test and categorical variables were analyzed using chi-square tests. *P value: <0.05,**P value: <0.01,***P value: <0.001

Primary endpoint:

At the start of Empagliflozin treatment, HBA1C, FBG, BMI, SBP and DBP mean were 10.28±2.23 (7.5 to 15.1), 278.53±104.43 (135 to 487), 30.68±3.80 (22 to 38.3), 147.63±25.08 (110 to 200) and 89.77±13.07 (60 to 120) respectively at baseline, which decreased to 9.29±2.00 (5.2 to 14.51; p=0.212), 221.79±106.04 (82 to 487; p =0.099), 28.40±4.25 (20.8 to 35.5; p =0.000), 134.47±14.03 (110 to 160; p =0.017) and 83.68±8.95(70 to 110; p =0.033) respectively after 12 weeks. After crossing over to Dapagliflozin, HBA1C, FBG, BMI, SBP and DBP mean were 9.87±1.56 (6.8 to 14; p =0.065), 172.37±59.44 (100 to 301; p =0.067), 28.80±4.85 (21.2 to 37.1; p =0.209), 130±14.91 (110 to 160; p =0.231) and 78.95±6.58 (70 to 95; p =0.079) respectively at 24 weeks.

 

 

 

At the start of Dapagliflozin treatment, HBA1C, FBG, BMI, SBP and DBP mean was 10.54±2.72 (7.43 to 14.9), 261.22±103.36 (134 to 440), 31.23±2.79 (26.6 to 36.2), 142.22±17.84 (120 to 180) and 83.89±9.16 (60 to 100) respectively at baseline, which decreased to 8.99±2.29 (6.7 to 14; p =0.005), 203.28±60.77 (99 to 300; p =0.008), 29.9±3.23 (24.9 to 36.3; p =0.000), 134.44±17.4 (110 to 180; p =0.11) and 85±11.76 (65 to 110; p =0.893) respectively after 12 weeks. After crossing over to Empagliflozin, HBA1C, FBG, BMI, SBP and DBP mean were 7.96±1.68 (6.2 to 12.9; p =0.005), 171.22±51.48 (85 to 311; p =0.003), 29.63±3.43 (24.4 to 35.7; p =0.759), 129.44±10.56 (120 to 160; p =0.179) and 81.67±6.18 (70 to 90; p =0.096) respectively at 24 weeks. There were no significant difference between the two periods in each group except for BMI in group AB (Table 3).

 

Table 3: mean change of group AB and group BA in period 1 and period 2:

	Group AB (n=19)				§p-value	Group BA (n=18)				§p-value
	Period1-Base	p-value	Period2-Period1	p-value		Period1-Base	p-value	Period2-Period1	p-value
HbA1C	-1.00±3.12	0.212	0.58±1.29	0.065	0.094	-1.55±2.15	0.005	-1.03±1.47	0.005	0.616
FBG	-56.74±149.9	0.099	-49.4±101.	0.067	0.573	-57.94±75	0.008	-32.06±40	0.003	0.237
BMI	-2.28±1.75	0.000	0.41±1.36	0.209	0.000	-1.33±0.85	0.000	-0.27±3.7	0.759	0.268
SBP	-13.16±21.87	0.017	-4.47±15.7	0.231	0.202	-7.78±24.7	0.11	-5.00±19.9	0.179	0.77
DBP	-6.05±11.25	0.033	-4.74±11	0.079	0.667	1.11±15.77	0.893	-3.33±11.63	0.096	0.74

HBA1C: Hemoglobin A1C, FBG: fasting blood glucose, BMI: body mass index, SBP: systolic blood pressure, DBP: diastolic blood pressure. variables were analyzed using PairedT-test or Wilcoxon Signed Ranked Test.

p-value: within group in one period. §p-value: within group between period 1 and period 2.

 

Over the treatment period of 12 weeks, the HbA1c levels were reduced by -1.01±2.43 (P=0.007) and -0.46 (p=0.420) in the Empagliflozin (25 mg/day) and Dapagliflozin (10mg/day) groups, respectively from baseline levels. More importantly, the HbA1c levels between groups at week 12 was lower but not significantly (P=0.433) in the Empagliflozin versus Dapagliflozin groups. A similar trend was determined for FPG levels which were reduced by -44.73mg/dL (P <0.003) and -53.56mg/dL (P<0.001)) in the Empagliflozin and Dapagliflozin groups, respectively from baseline levels. However, there was no difference in FBG between groups (P = 0.85) at 12 weeks. MBI levels were reduced by -1.3 (P < 0.012) and -0.44 (P < 0.068) from baseline levels, respectively. More importantly, Empagliflozin showed a significant greater reduction of BMI compared to Dapagliflozin (P = 0.044) at 12 weeks. SBP levels were reduced -9.19 (p = 0.012) and -6.08 (p = 0.035) from baseline levels, respectively. but there was no difference in DBP between groups (P = 0.757). DBP levels were reduced -4.73(p = 0.008) and -1.89 (p = 0.158) from baseline levels, respectively. Empagliflozin showed a greater reduction of DBP but not significantly compared to Dapagliflozin (P = 0.571) at 12 weeks (Table 4)(figure 2).

 

Table 4: Changes in Clinical Parameters from baseline with Empagliflozin or Dapagliflozin:

	Empagliflozin (n=37)			Dapagliflozin (n=37)			P- Value¶
	Baseline	Endpoint	p-value	Baseline	Endpoint	p-value
HBA1C	9.65±2.32 241.92±93.01 30.30±3.51 141.22±22.44 87.43±12.51	8.64±1.95 197.19±86.78 29.00±3.87 132.03±12.55 82.70±7.69	0.007 0.003 0.012 0.012 0.008	9.90±2.43 240.97±105.20 29.78±3.84 138.24±16.25 83.78±8.93	9.44±1.97 187.41±61.29 29.34±4.12 132.16±16.14 81.89±9.81	0.420 0.001 0.068 0.035 0.158	0.433 0.85 0.044* 0.757 0.571
FBG
BMI
SBP
DBP

HBA1C: Hemoglobin A1C, FBG: fasting blood glucose, BMI: body mass index, SBP: systolic blood pressure, DBP: diastolic blood pressure. Comparison of respective data between baseline and endpoint. The baseline of group Empagliflozin is the baseline of group AB and week 12 of group BA whereas the baseline of group Dapagliflozin is the baseline of group BA and week 12 of group AB. The endpoint of group Empagliflozin is week 12 of group AB and week 24 of group BA whereas the endpoint of group D is week 12 of group BA and week 24 of group AB. variables were analyzed using Paired t-test or Wilcoxon signed-rank test.

 

Figure (2:A) mean HbA1c for A and B groups at baseline and endpoint

 

Figure(2:B) mean FBG for A and B groups at baseline and endpoint

 

 

Figure(2:C) mean BMI for A and B groups at baseline and endpoint

 

Figure (2:D) mean SBP for A and B groups at baseline and endpoint

 

Figure (2:E) mean DBP for A and B groups at baseline and endpoint

 

DISCUSSION:

This randomized, crossover, clinical trial is the first to evaluate and compare the efficacy between Empagliflozin and Dapagliflozin during 2 periods of drug administration in Syrian patients as part of an add-on to metformin drug therapy to treat T2D patients with inadequate blood glucose control. Our results demonstrated that the 12-week administration of 25 mg Empagliflozin reduced significantly HbA1c, FBG, BMI, SBP and DBP levels whereas the 12-week administration of 10mg Dapagliflozin reduced HbA1c, FBG, BMI, SBP and DBP levels but it was a significant reduction only in FBG and SBP. And the only significant change from baseline was with Empagliflozin treatment compared with Dapagliflozin in BMI parameter.

 

 

 

Our results showed that Empagliflozin was relatively superior to Dapagliflozin in improving HbA1C, BMI and DBP in Diabetic patients but there were no significant differences in FBG and SBP.

 

Several studies have shown that treatment as add on metformin with Empagliflozin^17,18 or Dapagliflozin^23,24 decreased HbA1c levels. In our study, both Empagliflozin (∆HbA1c -1.01%) and Dapagliflozin (∆HbA1c -0.46) showed less improvement in reducing HbA1c than some previous studies, which may be due to the complementary interactive effect of the other OADs in those studies^22,25.

 

Similarly to our results, Previous studies have shown that there was a beneficial effect on reducing FBG because of using Empagliflozin^16,26 and Dapagliflozin^19–21,27. By contrast with a previous study that showed that Empagliflozin had presented a greater significant reduction of FBG compared to Dapagliflozin at 52 weeks²⁵. Our study showed that there was no significant difference between both drugs at 12 weeks. It is suggested that the difference in the duration between the two studies is a potential cause.

 

In addition to their effective control of blood glucose, SGLT2is show significant effects on other parameters, including bodyweight reduction and antihypertensive effect^28–36. consistent with these effects, our study demonstrated that systolic blood pressure was markedly reduced in the T2D patients for both drugs but Empagliflozin was more effective than Dapagliflozin in decreasing BMI during the course of the study period. Furthermore, DBP reduced in both groups but it was a significant reduction with the Empagliflozin group.

 

The results of this trial suggest that the lack of significant changes in HbA1c, BMI, and DBP with Dapagliflozin in our study might be attributable to the insufficient treatment period, and/or small sample size. Although this study has limitations as a single-centre study and short follow up, this study does provide new information about the effective use of SGLT2 inhibitors in T2D Syrian patients to control their blood glucose regulation. A previous study made the assumption that a single dose of Empagliflozin at 25mg/day is pharmacodynamically equivalent to dapagliflozin at 10 mg/day, it recommended that there may need to be dose modification researches to fully decide whether there is an advantage of Empagliflozin versus Dapagliflozin at least at the similar dose.

 

CONCLUSION:

Our study is a first step in developing a larger scale, multi-centre trial to show the efficacy of SGLT2is in Syrian diabetic patients and potentially use this drug regimen for specific patient populations who have T2D.

 

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

 

ACKNOWLEDGMENTS:

The authors would like to thank ALFARES Company and CITY PHARMA Company for their kind support during the study.

 

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Accepted on 27.09.2023           © RJPT All right reserved

Research J. Pharm. and Tech 2023; 16(10):4642-4648.