One therapeutic approach to treating type II diabetes is the idea of agonising the glucagon-like peptide-1 receptor
Type II diabetes is becoming an epidemic, as lifestyles become increasingly unhealthy. Improving diet and increasing exercise levels can help control the condition, at least to start with, but in the longer term drugs such as biguanides, sulfonylureas and insulin sensitisers have to be prescribed.
Another therapeutic approach is the idea of agonising the glucagon-like peptide-1 receptor. By activating this receptor, intracellular cyclic AMP is increased, resulting in an increase in insulin release in response to raised glucose levels; the release drops off again as glucose levels fall. But GLP-1 itself is metabolically degraded and its half life is just minutes, so more stable analogues such as Novo Nordisk’s liraglutide (Victoza) and Amylin’s exenatide (Byetta/Bydureon) were developed.
Another such analogue is under development at Lilly. Dulaglutide is a long-acting GLP-1 agonist being developed as a potential once-weekly treatment for diabetes.1 It is a GLP-1 immunoglobulin G Fc fusion protein that has extended pharmacokinetics and activity over the native protein.
In a randomised, placebo-controlled, double blind study in overweight or obese patients with Type II diabetes, 262 subjects who were also taking orally acting antidiabetic medicines were given once-weekly subcutaneous injections of placebo, or 0.5mg of dulaglutide for the first four weeks, followed by 1mg for 162 weeks, or double those doses, or 1mg for the whole 16 weeks.2 After the 16 weeks, reductions in HbA1c were significantly greater in those given dulaglutide than in those taking placebo. There was also a dose-dependent weight loss. The most common adverse events were nausea and diarrhoea.
It has also been investigated as monotherapy.3 A total of 167 patients were enrolled. They had previously been treated via lifestyle improvement measures, either with or without metformin, but metformin had been discontinued and they were otherwise naïve to antidiabetic medicines. They were given once weekly injections of placebo, or 0.1, 0.1, 1 or 1.5mg of dulaglutide. A significant dose-dependent reduction in HbA1c levels was seen in all doses, and dose-dependent reductions of fasting plasma glucose were also seen. In addition, there was a dose-dependent weight loss, but this was not significantly different from that seen in the placebo group. Again, the most common adverse events were nausea and diarrhoea.
The results of three Phase III trials have been released, ahead of planned regulatory submission later this year. These three trials compared dulaglutide therapy with exenatide, metformin and sitagliptin respectively. The exenatide comparative study was a 52-week randomised, placebo-controlled trial in which 978 patients with Type II diabetes were given metformin and pioglitazone plus placebo, exenatide, or once weekly 1.5mg injections of dulaglutide.4
In the metformin trial, which also ran for 52 weeks, 807 patients with early Type II diabetes were given either once weekly dulaglutide doses of 1.5mg, or metformin.5 And in the longer sitagliptin trial, 1098 patients with Type II diabetes who were also taking metformin were given 1.5mg weekly doses of dulaglutide, or sitagliptin or placebo.6
In all of these trials, dulaglutide was better than placebo and each of the comparator drugs in reducing HbA1c levels. In addition, those given dulaglutide exhibited significant weight loss compared with sitagliptin, and similar weight loss to patients taking exenatide and metformin in the other two trials. The most common adverse event was nausea, which was generally mild to moderate, and transient. In addition, dulaglutide caused low rates of hypoglycaemia.
1. W. Glaesner et al. Diabetes Metab. Res. Rev. 2010, 26, 287
2. P. Barrington et al. Diabetes Obes. Metab. 2011, 13, 434
3. G. Grunberger et al. Diabet. Med. 2012, 29, 1260
4. C. Wysham et al. Amer. Diabetes Assn 73rd Sci. Sessions, 2013 (21–25 Jun, Chicago), Abst 66-OR
5. G.E. Umpierrez et al. Amer. Diabetes Assn 73rd Sci. Sessions, 2013 (21–25 Jun, Chicago), Abst 69-OR
6. R.S. Weinstock et al. Amer. Diabetes Assn 73rd Sci. Sessions, 2013 (21–25 Jun, Chicago), Abst 1004-P