In the first ever trial done to test the efficacy of a combination drug exenatide and dapagliflozin therapy, researchers have found that the combination therapy casts a positive effect in curbing diabetes and cardiac symptoms in diabetes type 2 patients as compared to the metformin monotherapy.
This study was funded by AstraZeneca and conducted by Dr Juan P Frais from National Research Institute California and other researchers from AstraZeneca, Gaithersburg, USA.
The study was carried out as a double-blind, phase 3, randomized controlled trial for a duration of 28 weeks. It was conducted at multiple regions, with 109 locations in six nations. The patient population comprised of 695 adults aged 18 years or above with ineptly controlled glycemic levels (HbA1c 8–12% [64–108 mmol/mol]) even while receiving steady metformin single therapy at a dosage of ≥1500mg/day. The patients were randomly assigned the combination and monotherapy dosage regimens. The study was published in The Lancet Diabetes and Endocrinology.
A sample size of 231 patients received the combination therapy with exenatide and dapagliflozin, while another sample size of 231 patients received monotherapy with exenatide and the third group comprising 233 participants received monotherapy with dapagliflozin. The main objective or primary endpoint of the study was to observe reduction in HbA1c levels — the hemoglycated blood levels — from baseline till the end of therapy, over a period of 28 weeks.
Other endpoints or objectives which may be regarded as ancillary endpoints included any alteration in fasting plasma glucose from baseline at 2 weeks and at 28th week, change in plasma glucose levels following a meal or post prandial glucose levels at 28th week, percentage of subjects who observed less than 7% reduction in HbA1c levels at week 28, variation in weight by 28 weeks, percentage of patients who experienced ³5% weight loss by week 28 and modification or variation in systolic blood pressure by the end of trial duration, that is, at 28th week.
The study findings reported that the combination therapy with exenatide and dapagliflozin proved to be the most efficacious in terms of reducing the HbA1c levels – the primary endpoint or objective in diabetics over a period of 28 weeks. Moreover, the combination therapy was also superior to either of the monotherapy with exenatide or dapagliflozin in terms of achieving the secondary end-points effectively, that is, the combination proved highly fruitful in reducing both the fasting and post prandial plasma glucose levels, a large population of patients exhibited less than 7% (<53 mmol/mol) reduction in HbA1c levels, greater reduction in weight, larger proportion of subjects experienced more than 5% weight loss and attainment of normal systolic blood pressure levels.
However, the patients did experience adverse effects as cons of therapy which included gastrointestinal effects, mainly nausea and diarrhea, bumping at injection site and infection of urinary tract. However, these adverse effects were experienced by only a minor group of patients which comprised a total of ≥5% of subjects in any sample group. The combination was safe in terms of major adverse incidents which includes trivial and major hypoglycemic event.
Therefore, it was concluded that the combination therapy with exenatide and dapagliflozin resulted in rectification of several glycemic events with additional benefit of reducing the risk elements for cardiovascular events in such patient population — the type 2 diabetics who are inefficiently managed by metformin single therapy.
Both exenatide and dapagliflozin are injectable and oral hypoglycemic agents respectively, that are employed in type 2 diabetics. Exenatide is an analogue of the incretin hormones — the GLP-1 (glucagon-like-peptide-1) and glucose dependent insulinotropicpolypeptide. The incretin hormones are special hormones in the gut that are responsible for the release or secretion of 60-70% of insulin following a meal. They are, therefore, responsible for controlling glycemic levels following a meal by secreting large amounts of insulin. Exenatide is an analogue of GLP-1 hormone and acts as an GLP-1 receptor agonist and is administered subcutaneously via an injection.
On the other hand, dapagliflozin, more popular by the brand name Farxiga in US, was approved by FDA in January 2014 and belongs to gliflozin class that acts as a sodium – glucose cotransporter protein-2 inhibitor (SGLT-2 inhibitor). These proteins are accountable for 90% reabsorption of glucose from the kidneys back into the blood. By inhibiting these proteins, glucose absorption is inhibited and excess glucose is excreted in the urine.
Diabetes is ranked as one of the most challenging diseases among autoimmune and non-infectious diseases. Although, a number of oral hypoglycemic agents are available, there is still a large scope for innovative drug development for this defiant disease since it is associated with multiple complications and is a chronic condition with no absolute cure.