Dapagliflozin: The outcome of use as add-on therapy in real-life clinical setting -An Audit

Objectives: Dapagliflozin is the first novel sodium glucose co-transporter 2 inhibitor for the treatment of Type 2 diabetes. The aim of this audit was to evaluate its effectiveness and safety in a real-life clinical setting. Methods: We analyze data from four UK district general hospitals on patients initiated on dapagliflozin. HbA1c, weight and daily insulin dosage was recorded at baseline and 6 months follow-up. Results: At baseline, mean HbA1c was 82±19.21mmol/mol(9.7%) and mean weight was 102±18.1kg. The average reduction in HbA1c at 6 months was 13±7.23 mmol/mol (1%) whereas the average reduction in weight was 2 ±2.02 kg.. A mean reduction in daily insulin requirement by 12±8.3 units at 6 months compared to baseline was noted. There were certain complications in patients taking insulin and gliclazide including candidiasis, urinary tract infection and hypoglycaemia, and 4% patients discontinued dapagliflozin due to side effects. Conclusion: Our results confirm that dapagliflozin can be used safely and effectively in a real-life setting.


Introduction
The progressive nature of type 2 diabetes mellitus (T2DM) requires increasingly intensive anti-diabetes regimen over time.Dapagliflozin is the first novel sodium glucose co-transporter 2 (SGLT2) inhibitor approved and introduced into clinical practice in the United Kingdom towards the end of 2012, and in Pakistan in 2017.[3][4] The current study was planned to assess efficacy, tolerability and safety of dapagliflozin in a real-life clinical setting, and to compare its correlation with various clinical trials involving dapagliflozin.

Patients and Methods
The non-randomised, multi-centre, real-world, observational and prospective study was conducted from July 2013 to December 2014 at the endocrine department of four different National Health Service (NHS) district general hospitals in midlands region of United Kingdom.Ethical approval was not considered necessary as it was deemed a quality improvement audit in collaboration with different NHS Trust facilities to determine the appropriate use of dapagliflozin in a clinical setting.Electronic record forms were retrieved of people with Type 2 Diabetes mellitus who were initiated with dapagliflozin 10mg once a day as an add-on treatment in the out-patient clinical settings.
The records of all people prescribed dapagliflozin were analysed, and data related to time, age, gender, duration of diabetes, HbA1C and weight was collected for each patient at baseline and at 6 months.Data was also collected on whether or not patients were already on insulin at the time of initiating dapagliflozin, modification of insulin dose after starting dapagliflozin, and side effects of dapagliflozin at subsequent follow-up visits at 3 and 6 months.Changes from baselines for HbA1c and weight were calculated.In cases where dapagliflozin had to be stopped due to side effects, data from subsequent visit was excluded from analysis.
Side effects were recorded for 23(10%) people, with genital candidiasis being the most common seen in 9 patients.The other common side effects were urinary tract infection that was seen in 8 patients and dehydration as evidence by raised urea levels and postural drop was seen in only 5 patients.Of the 5(21.7%)people who experienced hypoglycaemia, 4(80%) were on insulin and 1(20%) was on gliclazide.There was no documented instance of euglycaemic ketoacidosis in the cohort.

Discussion
Dapagliflozin is an SGLT2 inhibitor that has an insulinindependent mechanism inhibiting SGLT2 in the proximal tubule of the kidney, preventing glucose re-absorption. 5,6he resulting glycosuria also promotes weight-loss as well as urinary sodium-loss, which, along with weight reduction and osmotic diuresis, may be responsible in part for the BP-lowering effects observed. 7e current study on the use of dapagliflozin in real-life clinical setting demonstrated that dapaglifliozin was effective at reducing HbA1c and weight.2][3][4] The effectiveness of dapagliflozin in the current study was greater with regards to higher reduction in HbA1C and weight.This is possibly due to higher baseline HbA1C as well as the fact that dapagliflozin was continued only when it was clinically effective.In fact, the greatest improvement in HbA1c and weight was seen in those with the higher HbA1C and weight at the baseline.Our study also demonstrated that  GLP-1: Glucagon-like peptide-1.
HbA1c: Glycated haemoglobin.a significant number of patients could either reduce or stop other diabetic medications, including GLP-1 agonist and insulin, leading to additional cost benefits from a pharmaco-economic perspective.
The current study also revealed that dapagliflozin can be safely prescribed in secondary-care setting with only 10% patients taking dapagliflozin reporting any side effects.However, those who experienced various side effects were likely to continue to take dapagliflozin with only 4% of the cohort discontinuing dapagliflozin due to side effects.[3][4] The current study has a number of limitations, such as no control group or placebo arm for comparison as well as some missing data for the outcome measures of HbA1c and weight that represent the difficulties in measuring and documenting these parameters in routine clinical practice.The study also did not include SBP measurement in data as only 13 patients has SBP monitored at both baseline and 6-month follow-up.Also, routinely collected data to assess the prevalence of side effects is likely to lead to some underestimation of frequency, as minor side effects may not be reported in clinics.

Conclusion
Dapagliflozin was found to be effective for use in clinical practice for the reduction of HbA1C and weight.
There was lower incidence of side effects compared to clinical trials.There was also a considerable reduction of the use of other oral anti-diabetes medication, indicating cost-effectiveness of dapagliflozin as a novel glucose-lowering agent.

Figure- 1 :
Figure-1: Study flowchart showing patient distribution and final patient analysis for HbA1c and weight loss at 6 months.

Table - 1
: Response to dapagliflozin treatment at 6 months in patients with type 2 diabetes based on baseline glycaemic control, baseline body weight and on insulin versus non-insulin users (real world data).

Table - 2
: Modification in concurrent diabetes medications during the follow-up period in patients who tolerated dapagliflozin.