Pakistan is ranked 4th globally in terms of percentage of population with diabetes mellitus (DM) as the prevalence of DM is around 26% in Pakistan.1 Appropriate management options are required to manage this large proportion of population aiming timely prevention of diabetes linked microvascular and macrovascular complications.2

Dapagliflozin is known to be a selective “sodium-glucose cotransporter type-2 inhibitor (iSGLT2)” that blocks glucose resorption in the proximal tubule of the kidneys which increase urinary glucose excretion that helps in reduction of blood glucose levels.3,4 Dapagliflozin has been licensed in Pakistan since 2017 for the management of type-2 diabetes mellitus (T2DM).5,6 Systemic review conducted by Baker WL et al described Dapagliflozin to result in reduction in systolic blood pressure by 4 to 5 mmHg while it also resulted in reduction in 1.7 kg weight loss as well.7 Other researchers have found Dapagliflozin to raise high-density lipoprotein cholesterol (HDL-c) as 1.8-4.4%8 while it has been observed to result in reducing triglyceride concentration by 2.4-6.2%.9 Researchers are currently evaluating roles of Dapagliflozin among patients having pre-diabetes and other types of diabetes.9,10

There is scarcity of local data about the safety and effectiveness of Dapagliflozin. As Pakistani population have differences in genetic, demographic, cultural and life-style characteristics when compared to other parts of the world, it is vital to find out the role of Dapagliflozin in our local population. The present study was conducted to gather clinical data regarding weight reduction, glycemic control and safety of Dapagliflozin oral tablets in T2DM patients from South Punjab, Pakistan.

This prospective clinical trial was conducted at Department of Medicine, Bahawal Victoria Hospital, Bahawalpur from July 2019 to June 2020. Approval from Institutional Ethical Committee was taken for this study. Written consent was sought from all study participants.

Sample size was calculated by clincalc.com for 0.752 anticipated mean of outcome (i.e. reduction in HbA1c) by use of study drug using 0.77±0.11 HbA1c reduction from published clinical study.11 Sample size calculated was 312 at 0.05 α, using 80% power. By equating dropout rate 22.1% from previous study for the calculated sample size, the final adjusted sample size would be n = 400 using dropout rate equation as: Dropout Rate, N = n / (1‐ (z/100)), where N= final adjusted sample size, n= calculated sample size and Z%= dropout rate. So, finalized adjusted sample size was 400.

A total of 400 patients of genders aged above 18 years having type-2 diabetes mellitus were enrolled. All patients had BMI above 25 kg/m2. All patients did not have any known hypersensitive to Dapagliflozin or any of its ingredients. Patients having type-I diabetes, or those with complaints of urinary tract infections, genital infections, or eGFR < 60 mL/min/1.73 m², having end stage renal disease or going through dialysis were were excluded. All pregnant females or those patients who had suspected ketoacidosis were also excluded from this study. Patients losing planned follow ups were excluded from the final analysis.

Demographic data of all patients like gender, age, weight, height, disease related information, blood pressure, comorbid conditions, number of concomitant medications and number of anti-hyperglycemic agents were noted. Baseline HbA1c, fasting blood sugar (FBS) and random blood sugar (RBS) levels were also recorded. Dapagliflozin prescribed as 5mg or 10mg was also noted. Patients whose blood sugar levels were not controlled on 5 mg in 2 weeks were given 10 mg once daily. Patients were asked to follow up after every 2 weeks up till 24 weeks. Change in weight, HbA1c, FBS, RBS and blood pressure was recorded during the follow ups.

Data was analyzed using SPSS version 26.0. Qualitative variables like gender area of residence and past history were represented as frequency and percentages. Quantitative variables like age, weight, height, systolic blood pressure (SBP), diastolic blood pressure (DBP), number of comorbidities, concomitant medications, anti-hyperglycemic agents, RBS, FBS and HbA1c were calculated as mean and standard deviation. Paired sample t-test was employed to compare data between baseline and follow ups considering p value less than or equal to 0.05 as significant.

Out of a total of 400 patients enrolled, 238 (59.5%) were female. Overall, mean age was 48.06+10.38 years. There were 352 (88.0%) patients with known history of T2DM whereas 48 (12.0%) were newly diagnosed cases of T2DM. In known T2DM patients, mean duration of T2DM was noted to be 4.51+2.1 years. Mean baseline body weight was noted to 78.81±15.67 kg. Mean HbA1c (%) was recorded to be 9.14+2.12. Table 1 is showing baseline characteristics of all 400 patients enrolled for this study.

Table 2 is showing comparison of body weight at baseline and during various follow ups among study participants. Statistically significantly reduction in body weight was noted at 4 weeks, 12 weeks and 24 weeks when compared to baseline values (p<0.05).

Table 3 is highlighting comparison of HbA1c levels between baseline and 12th week and 24th week. Statistically significant reduction in HbA1c levels were recorded among study participants at 12th week (change in HbA1c=0.42+0.75, p=0.0022) and 24th weeks (change in HbA1c=0.85+0.67, p<0.0001). By the end of study period, there were 58 (21.6%) patients who achieved HbA1c < 7%

Mean fasting blood sugar at baseline was noted to be 221.99+85.27 at baseline while it was found to be 154.50+24.36 at the end of the study period (24th week) (p=<0.0001). Mean random blood sugar was noted to be 267.58+74.46 mg/dl at baseline while it was found to be 189.42+38.77 at the end of the study period (24th week) (p=<0.0001). Mean systolic blood pressure was noted to be 142.24+21.47 mmHg at baseline while it was found to be 138.50+16.47 mmHg at the end of the study period (24th week) (p=0.0160). Mean diastolic blood pressure was noted to be 92.14+7.14 mmHg at baseline while it was found to be 90.40+5.48 at the end of the study period (24th week) (p=0.0008).

In terms of side effects, hypoglycemia was reported in 12 (3.0%) patients, polyuria 10 (2.5%), urinary tract infection 5 (1.3%) and genital infection 4 (1.0%) while remaining patients did not report any side effects. Five (1.3%) patients reported with foot ulcer within 4 weeks after starting the treatment and treatment was stopped in all those patients. There were 9 (2.3%) patients who left the dapagliflozin treatment due to no benefits.

Present study is the 1st one from South Punjab, Pakistan that evaluated effectiveness and safety and of dapagliflozin in T2DM patients. We noted significant reduction in body weight, HbA1c, FBS, RBS, SBP and DBP in our study participants. It is also worth noting that 21.6% of patients achieved HbA1c < 7% after initiating dapagliflozin.

In this study, we found mean reduction of 2.30+1.49 kg body weight at 4th week (p=0.0369), 3.41+1.93 kg at 12th week (p=0.0048) and 2.81+3.96 kg at 24th week (p=0.0147). Our results are quite consistent with a previous local study conducted by Kamin M et al from Islamabad who evaluated effectiveness of dapagliflozin in terms of body weight reduction and found dapagliflozin to result in 1.95+3.03 kg exact body weight reduction after 24 weeks of treatment in T2DM patients.12 List JF et al also noted dapagliflozin treatment to enhance hyperglycemia and assist weight loss among patients having T2DM by inducing controlled glucosuria with urinary loss of approximately 200-300 kcal/day.13 Some researchers evaluating older patients with T2DM having concomitant cardiovascular disease have found dapagliflozin to improve glycemic control and well as weight reduction.14,15

In the present work, statistically significant reduction in HbA1c levels were recorded among study participants at 12th week (change in HbA1c=0.42+0.75, p=0.0022) and 24th weeks (change in HbA1c=0.85+0.67, p<0.0001). Past data endorse dapagliflozin to result in reduction in HbA1c levels which are quite similar to other oral anti-hyperglycemic medications but dapagliflozin has additional advantages in terms of beneficial effects on T2DM related comorbid conditions like cardiovascular diseases.16,17 Some studies have also evaluated possible role of dapagliflozin in raising risk of cardiovascular risk in T2DM patient and found no associated risks involved.18,19

In the present study, no serious side effects were recorded among study participants as hypoglycemia, polyuria and urinary tract infection were the most common side effects reported in 3.0%, 2.5% and1.3% patients respectively. Past studies have reported occurrence of hypoglycemia in about 4% cases using oral dapagliflozin and our findings are consistent with the past data.12,20 It is important to note that no major side effects or hypoglycemic episodes were noted in the present study participants. Five (1.3%) patients reported with foot ulcer within 4 weeks after starting the treatment and treatment was stopped in all those patients. We are not sure that the relation between occurrence of diabetic foot ulcer after starting dapagliflozin is casual or not. We are living in high temperature area and many patients are working in the field. In future studies we may be considering high risk patients for diabetic foot.

The present study had some limitations as well. We were unable to evaluate the impact of concomitant anti-hyperglycemic agents on the outcomes measured in this study. Also, we did not analyze the decrease or increase in insulin dosage among patients who were suing insulin. Patients missing out on follow ups could have influenced the outcome as some of them are believed to have lost due to lack in efficacy of the treatment so their inclusion could have further strengthen the authenticity of the outcome data.

Dapagliflozin was found to have good efficacy in terms of body weight reduction and improvement in glycemic control among patients with T2DM. Overall, safety profile of dapagliflozin was good.

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