Diabetes currently constitutes around 10% of the total health resource expenditure in the UK and is predicted to account for around 17% in 2035/2036 if current trends are continued.1 The need for improved antidiabetic regimens is clear but, to date, few studies have investigated the use of multiple agents with complementary mechanisms of action. Glucagon-like-peptide 1 (GLP-1) receptor agonists, and sodium glucose cotransporter 2 (SGLT-2) inhibitors have been among the most exciting developments in diabetes in the last decade. Different mechanisms underlie behind the glucose-lowering action of these two drug classes. GLP-1 receptor agonists exert their glucose-lowering effects by a number of actions, including enhanced glucose-dependent insulin secretion, suppressed inappropriately elevated glucagon secretion, reduction of food intake and body weight, and slowing of gastric emptying.2 By contrast, SGLT-2 inhibitors regulate glucose levels by inhibition of renal glucose reabsorption, and increased urinary glucose excretion through selective inhibition of renal SGLT 2.3 It is therefore not surprising that researchers are investigating the possible synergistic effect of combined therapy with these two drug classes.
The DURATION 8 trial aimed to determine whether the combination of the GLP-1 receptor agonist exenatide2 and the SGLT2 inhibitor dapagliflozin4 was more effective than either drug alone in patients with type 2 diabetes (T2D) inadequately controlled on metformin monotherapy. DURATION-8 was a 28-week, multicentre, double blind, randomised, active-controlled Phase III trial. 5 A total of 695 participants with T2D and HbA1c levels of 8%-12% despite metformin therapy were randomly assigned (1:1:1) to receive once-weekly exenatide 2 mg by subcutaneous injection plus once-daily dapagliflozin 10 mg oral tablets, exenatide with dapagliflozin-matched oral placebo, or dapagliflozin with exenatide-matched placebo injections.
Results at 28 weeks showed that exenatide plus dapagliflozin significantly reduced HbA1c from baseline compared with exenatide alone (-0·4%; p=0·004) or dapagliflozin alone (-0·6%; p<0·001). Exenatide plus dapagliflozin was also significantly superior to either drug alone in terms of reductions in fasting plasma and postprandial glucose, proportion of patients with an HbA1c <7·0%, weight loss and reductions in systolic blood pressure (all p≤0·025). The combination was well tolerated and the incidence of adverse events was similar in all groups. The most common adverse events (AEs, ≥5% of patients in any group) were diarrhoea, injection-site nodules, nausea, and urinary tract infections.
Data presented during the 77th Scientific Sessions of the American Diabetes Association (ADA) on June 12, 2017, in San Diego, California show that the benefits of combined exenatide and dapagliflozin are maintained at one year. Levels of HbA1c dropped by 1.75% in the exenatide/dapagliflozin arm, 0.37% more than with exenatide (p<0.01) and 0.52% more than with dapagliflozin (p<0.01). In addition, reductions in fasting plasma glucose levels of 63 mg/dL were seen with the combined therapy, compared with 45 mg/L with exenatide and 40 mg/L with dapagliflozin (p<0.001 for both) Combined therapy also reduced 2-hour postprandial glucose levels by 82 mg/dL compared with 63.6 mg/dL with exenatide (p<0.01) and 59 mg/L with dapagliflozin (p<0.001). In addition, the combined therapy group lost an average of 3.3 kg over 1 year and had mean reductions in systolic blood pressure of 4.5 mm. These reductions were significantly higher than with exenatide but not with dapagliflozin. There was a lower requirement for rescue therapy in the exenatide plus dapagliflozin group (27%) than in the exenatide (32%) or dapagliflozin groups (38%)Similar rates of serious AEs, gastrointestinal AEs, and AEs leading to treatment discontinuation were reported in all groups. Around 4% of patients in each group discontinued treatment because of AEs. Combined therapy was associated with slightly higher rates of injection-site nodules (9%) and headaches (6%), compared with exenatide or dapagliflozin plus placebo. No episodes of severe hypoglycaemia or acute renal failure were reported. Glomerular filtration rates fell by a mean 2 mL/ min per 1.73 m2 after 1 year of exenatide/dapagliflozin, by 1.2 mL/min per 1.73 m2 with exenatide, and by 0.8 mL/min per 1.73 m2 with dapagliflozin..
In an editorial accompanying the release of the 28-week data,6 Michael A Nauck, MD, and Juris J Meier, MD, of St Josef Hospital, Bochum, Germany commented that these two agents are not the ones that have shown significant cardiac benefit to date (i.e., liraglutide [Victoza, Novo Nordisk]7 and empagliflozin [Jardiance, Boehringer Ingelheim/Lilly].8 The results of the cardiovascular-outcomes trials for exenatide (EXSCEL)9 and dapagliflozin (DECLARE-TIMI 58)10 are not expected until 2018 and 2019 respectively. It will be interesting to discover whether the cardiovascular benefit of the combination of GLP-1 receptor agonists and SGLT2 inhibitors is greater than that provided by either drug alone.
It is not known how readily people with T2D would tolerate multiple glucose-lowering therapies in everyday life; the majority of them are also on other multiple medications, for example, statins and antihypertensives. More data, including real-world studies, are needed before such regimens gain widespread use. However, this study has demonstrated that patients with T2D who need further improvement in glycaemic control can be considered for a combined GLP-1 receptor agonist/SGLT-2 inhibitor combination.