Exenatide LAR (a once weekly GLP-1 analogue) has just been approved for use in Europe. Compared with Sitagliptin and pioglitazone this achieves greater reduction in HbA1c over time, whilst also achieving significantly greater weight loss. Potential gains are persistently increased exenatide levels with the potential for greater therapeutic effect at the expense of a bigger needle and possible enhanced risk of side effects.
Forthcoming there is a hybrid GLP-1 and glucagon receptor agonist. A number of preclinical studies have shown that this approach has interesting potential. As a peptide therapy, this is an injection. However for those who prefer tablets, there are also oral non-peptide GLP-1 agonists in development.
Recently approved DPP-4 inhibitors are Linagliptin and Alogliptin which have altered pharmacodynamics, but generally the same capability as present DPP-4 agents.
Glucokinase activators in development will potentially reduce hyperglycaemia with modulated hypoglycaemia risk. The GPR119 agonists also offer potential as they will increase GLP-1 production and insulin secretion whilst reducing glucagon secretion. Additionally, selective inhibition of glucocorticoid effect may offer an interesting therapy in type 2 diabetes and agents are under investigation using 11beta- HSD1 inhibition.
INT131 is a selective PPAR gamma modulator that will alter the co-activators that come into play in this field of therapy, and thus reduce HbA1c whilst also reducing current side effects. There are also insulin receptor activators and sensitisers under investigation at present.
SGLT-2 co-transporter inhibitors are now available and reduce the re-uptake of glucose in the proximal tubule in the kidney and increase glucose elimination in the urine. This can eliminate >180 grams of glucose per day. In clinical trials in this class, dapagliflozin added to metformin offers sustained improvement in HbA1c reduction.
Finally new analogue insulins are about to become available. Degludec is an ultra-long acting insulin analogue that can be given just three times per week in DM2. Added to metformin in DM2 it shows the same efficacy as glargine without the need for as many injections.
Thus there is a plethora of new agents coming in type 2 diabetes management and generalists and specialists will have much to learn if they are to stay ahead.
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