Some days ago, I had the occasion to review recent data from NHANES. They showed a diabetes prevalence figure in the USA very similar to that previously shown by the Di@bet.es study in Spain some three years ago: a 14% of the whole population, including a number of people who still do not know the existence of the disease. The trend is to increase, because of a number of reasons that are out of the scope of this note.
This way, Type 2 diabetes – along with hypertension and other cardiovascular risk factors – constitutes a very serious threaten for public health, for its clear-cut association with overweight and aging – both of them problems that seem to have reached alarming proportions in our societies -.
But all of this is not news. May be it was so some years ago, and so it lingers today. During years, these facts have filled the pages of the medical and general press, and probably they impress nobody for the time being.
Even so, we have some new elements able to complicate – or to alleviate, depending on the point of view – the question.
The novelty is the variety of therapeutic tools at our disposition in the world of today.
Going back to 1990, we could probably say that therapy for Type 2 diabetes was stable, inefficacious and cheap. Even metformin was marginalized, if not overtly condemned by academic authorities. But, some time after, a series of changes was undertaken – upon more or less solid scientific grounds -, that pretended to put aside old tools and to inaugurate a new world of molecules and mechanisms, offering new paradigms and expectations.
In the world of today, old slow-acting insulins (protamin-retarded) seem to be condemned to oblivion, like sulphonylureas. In the place of the formers, there emerges the reign of analogs of slow-acting insulin (glargine, detemir and others to come). Likewise, here you have “wise” secretagogues, able to stop their stimulus in the face of normo or hypoglycemia (the gliptins). GLP-1 analogs consolidate their position, especially in the obese individuals. And some KOLs launch the idea of triple therapy from the start of the diabetes (pioglitazone, GLP-1 analog and metformin) as the best way to hamper the beta cell deterioration.
At the same time, you have points of view that claim that these changes are expensive – very expensive indeed -, that they sustain their position upon improvements of surrogate variables in highly controlled settings, and that any impact upon robust health outcome – e.g. whole mortality or cardiovascular mortality – is lacking These voices tend to question any advantaged offered by new tools, especially when they are related with the expense they mean.
Notwithstanding, this controversy has just been defied. Recent publication of EMPA-REG study in The New England Journal of Medicine poses a significant turmoil in this field. Empagliflozin is a drug acting by means of a novel mechanism – theoretically not related with cardiovascular disease -, and offers a protection of 14% in the combined end point of death from cardiovascular causes, nonfatal myocardial infraction, or nonfatal stroke. Up to this moment, to my knowledge, no antidiabetic drug has been able to prove a result of this kind.
Still, it’s got a long way ahead. We’ll have to wait for comments, editorials and critical analysis. And, more importantly, we’ll have to wait for the confirmation from other studies now on their way, performed with other molecules belonging to the same therapeutic group. Nevertheless, so relevant a finding leaves us basically with a simple dilemma:
1) Results are confirmed. That is to say that something especially new emerges in the Type 2 diabetes therapeutic arsenal. Then, we probably have a new paradigm that makes treatment algorithms to be reconsidered. But we should take into account that the new drug is twenty times more expensive – in Spain – than conventional alternatives. And it should be considered that the putative indication – Type 2 diabetes with cardiovascular disease – affects a very significant proportion of the general population – and growing each year -. In any case, an earthquake for every health system budget is anticipated.
2) Results are not confirmed. That is to say that something is wrong in a clinical trial with a respectable n, respectable observation period and respectable design and analysis. And – last but not least -, appeared in a respectable top journal – top of the top of clinical medicine -. If this is not true or it is “questionable”, one could wonder if the same could be applied to every finding appeared in the pages of top rank journals. The Bible, this way, could prove “questionable”. And with it, you could project a cast of doubt upon the very foundations of everything that is commonly believed in Scientific Medicine. In that sense, a scientific earthquake could be anticipated.
Thus, EMPA-REG study constitutes an earthquake, whatever the final interpretation, and makes us stay attentive to the end of the story. And I do not think that this position is exaggerated: I did not see a study alike in twenty-five years in this field. The UKPDS was not so impressive, at least in its cardiovascular outcome.