Diabetes: Incretin Enhancers, Mimetics and More

As I wander from session to session here at the EASD in Stockholm, I continue to wonder about the pipeline of new antidiabetic medications – many of which are only now starting to find their way onto formularies.

For example, the recognition of the important role of enteric hormones (incretins) in the regulation of insulin release and other metabolic functions has led to a scramble for novel pharmacological strategies to manipulate this system.

Essentially two strategies have emerged, both primarily targeting glucagon-like peptide (GLP) 1 – incretin enhancers and incretin mimetics.

The first class of drugs, called “gliptins”, work by inhibiting DPP-IV (dipeptidyl peptidase-4), the primary enzyme that degrades naturally secreted GLP-1, thereby increasing its availability to act on the islet cell and other organs. Given the action of GLP-1 to enhance insulin secretion (in response to a meal), to centrally reduce appetite and to decrease gastric emptying, it is notable that the use of DPP-IV inhibitors is neither associated with hypoglycemia nor with weight gain.

The other class of drugs targeting this system are GLP-1 mimetics, which allow supra-physiological stimulation of this system, thereby not only improving glycemic control but actually promoting weight loss.

While studies on the use of GLP-1 mimetics specifically targeting obesity are currently underway, DPP -IV inhibitors and GLP-1 analogues are already indicated in patients not controlled on one oral agent, and may perhaps be used as a alternative for metformin intolerant patients.

In one talk, my friend and colleague Ele Ferrannini (Pisa, Italy), talked about the future of antidiabetic agents. Just a decade ago, the only antidiabetic agents apart from insulin were sulphonyl ureas, metformin and acarbose. Today, we already have 11 different classes of antidiabetic agents with a wide range of modes of action and significantly different side effect profiles.

These include thiazolidinediones, glinides, amylin mimetics, GLP-1 agonists, DPP-4 inhibitors, bile acid sequestrants, and bromocriptine.

Despite all of these medications, monotherapy (with the exception of unlimited doses of insulin) is rarely effective in fully controlling diabetes. This means that most patients need combination treatment to reach treatment targets.

However, given the countless possible combination regimens, it is unlikely that we will ever see clinical trials for all combinations. So the issue of which agents to combine, will likely remain a matter of opinion, debate and marketing “spin” for the foreseeable future.

However, things are about to get even more confusing, as there are still more classes of antidiabetic agents likely to make it to market in coming years.

These include SGLT2 inhibitors, 11ß-HSD-1 inhibitors, GK activators, GPR119 agonists, DGAT-1 inhibitors, Dual PPARγ,α agonists, panPPARs, SPARMs, Glucagon receptor antibodies, phosphorylase inhibitors, F-1,6-bisphosphonate inhibitors, and PTB-1b inhibitors, to name a few.

One can only imagine the billions of dollars flowing into these drug development programs, clearly a reflection of both the medical need and the potential earnings to be made given the expected half-billion people likely to have diabetes with in the next few decades.

That is of course, if we assume that efforts to prevent and treat obesity continue to be unsuccessful.

In fact (some would say sadly), despite all of these “exciting” new medications, the only “cure” for type 2 diabetes today remains bariatric surgery – not something one can recommend to 15% of the population.

Still, I can vividly see my surgical colleagues shaking their heads in disbelief, wondering why anyone would want more drugs for a condition that, according to them, can be “cured” with a “routine” surgical procedure.

From a pharmaceutical perspective, of course the hope is that eventually medications will be found that will be so effective and safe that they will eventually make “diabetes surgery” obsolete – at this time I would rather predict that we will likely see an explosive expansion of diabetes surgery and that this trend will continue till we get a better handle on non-surgical obesity treatments.

After all, treating type 2 diabetes is essentially “palliative care” – it is what you do, when you can’t treat obesity.

Stockholm, Sweden

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